Journal ArticleJ Mol Biol · September 15, 2024
Knowing the conformational ensembles formed by mismatches is crucial for understanding how they are generated and repaired and how they contribute to genomic instability. Here, we review structural and energetic studies of the A-C mismatch in duplex DNA an ...
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Journal ArticleStructure · September 5, 2024
Conformational dynamics is crucial for the biological function of RNA molecules and for their potential as therapeutic targets. This meeting report outlines key "take-home" messages that emerged from the presentations and discussions during the CECAM works ...
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Journal ArticleJ Phys Chem B · May 2, 2024
Elucidating how damage impacts DNA dynamics is essential for understanding the mechanisms of damage recognition and repair. Many DNA lesions alter their propensities to form low-populated and short-lived conformational states. However, NMR methods to measu ...
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Journal ArticleNucleic Acids Res · March 21, 2024
Many biochemical processes use the Watson-Crick geometry to distinguish correct from incorrect base pairing. However, on rare occasions, mismatches such as G·T/U can transiently adopt Watson-Crick-like conformations through tautomerization or ionization of ...
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Journal ArticleNat Commun · December 19, 2023
Sparse and short-lived excited RNA conformational states are essential players in cell physiology, disease, and therapeutic development, yet determining their 3D structures remains challenging. Combining mutagenesis, NMR spectroscopy, and computational mod ...
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Journal ArticleJ Am Chem Soc · October 25, 2023
Knowing the 3D structures formed by the various conformations populating the RNA free-energy landscape, their relative abundance, and kinetic interconversion rates is required to obtain a quantitative and predictive understanding of how RNAs fold and funct ...
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Journal ArticleNat Chem Biol · July 2023
Replicative errors contribute to the genetic diversity needed for evolution but in high frequency can lead to genomic instability. Here, we show that DNA dynamics determine the frequency of misincorporating the A•G mismatch, and altered dynamics explain th ...
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Journal ArticleProc Natl Acad Sci U S A · June 20, 2023
In the mid-1930s, the English mathematician and logician Alan Turing invented an imaginary machine which could emulate the process of manipulating finite symbolic configurations by human computers. His machine launched the field of computer science and pro ...
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Journal ArticleNature · May 2023
Cellular processes are the product of interactions between biomolecules, which associate to form biologically active complexes1. These interactions are mediated by intermolecular contacts, which if disrupted, lead to alterations in cell physiology. Neverth ...
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Journal ArticleFrontiers in molecular biosciences · January 2023
Numerous biological processes and mechanisms depend on details of base pairing and hydrogen bonding in DNA. Hydrogen bonds are challenging to quantify by X-ray crystallography and cryo-EM due to difficulty of visualizing hydrogen atom locations but can be ...
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Journal ArticleCell Rep · August 30, 2022
N6-methyladenosine (m6A) is deposited co-transcriptionally on thousands of cellular mRNAs and plays important roles in mRNA processing and cellular function. m6A is particularly abundant within the brain and is critical for neurodevelopment. However, the m ...
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Journal ArticleProc Natl Acad Sci U S A · July 26, 2022
The majority of base pairs in double-stranded DNA exist in the canonical Watson-Crick geometry. However, they can also adopt alternate Hoogsteen conformations in various complexes of DNA with proteins and small molecules, which are key for biological funct ...
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Journal ArticleProc Natl Acad Sci U S A · June 14, 2022
Thermodynamic preferences to form non-native conformations are crucial for understanding how nucleic acids fold and function. However, they are difficult to measure experimentally because this requires accurately determining the population of minor low-abu ...
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Journal ArticleProc Natl Acad Sci U S A · March 8, 2022
SignificanceUnderstanding and treating neurological disorders are global priorities. Some of these diseases are engendered by mutations that cause defects in the cellular synthesis of transfer RNAs (tRNAs), which function as adapter molecules that translat ...
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Journal ArticleNucleic Acids Res · December 2, 2021
Watson-Crick base pairs (bps) are the fundamental unit of genetic information and the building blocks of the DNA double helix. However, A-T and G-C can also form alternative 'Hoogsteen' bps, expanding the functional complexity of DNA. We developed 'Hoog-fi ...
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Journal ArticleCurr Opin Struct Biol · October 2021
Nucleic acids do not fold into a single conformation, and dynamic ensembles are needed to describe their propensities to cycle between different conformations when performing cellular functions. We review recent advances in solution-state nuclear magnetic ...
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Journal ArticleNat Commun · August 31, 2021
N6-methyladenosine (m6A) is a post-transcriptional modification that controls gene expression by recruiting proteins to RNA sites. The modification also slows biochemical processes through mechanisms that are not understood. Using temperature-dependent (20 ...
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Journal ArticleRNA · January 2021
Identifying small molecules that selectively bind an RNA target while discriminating against all other cellular RNAs is an important challenge in RNA-targeted drug discovery. Much effort has been directed toward identifying drug-like small molecules that m ...
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Journal ArticleJ Mol Biol · September 15, 2024
Knowing the conformational ensembles formed by mismatches is crucial for understanding how they are generated and repaired and how they contribute to genomic instability. Here, we review structural and energetic studies of the A-C mismatch in duplex DNA an ...
Full textLink to itemCite
Journal ArticleStructure · September 5, 2024
Conformational dynamics is crucial for the biological function of RNA molecules and for their potential as therapeutic targets. This meeting report outlines key "take-home" messages that emerged from the presentations and discussions during the CECAM works ...
Full textLink to itemCite
Journal ArticleJ Phys Chem B · May 2, 2024
Elucidating how damage impacts DNA dynamics is essential for understanding the mechanisms of damage recognition and repair. Many DNA lesions alter their propensities to form low-populated and short-lived conformational states. However, NMR methods to measu ...
Full textLink to itemCite
Journal ArticleNucleic Acids Res · March 21, 2024
Many biochemical processes use the Watson-Crick geometry to distinguish correct from incorrect base pairing. However, on rare occasions, mismatches such as G·T/U can transiently adopt Watson-Crick-like conformations through tautomerization or ionization of ...
Full textLink to itemCite
Journal ArticleNat Commun · December 19, 2023
Sparse and short-lived excited RNA conformational states are essential players in cell physiology, disease, and therapeutic development, yet determining their 3D structures remains challenging. Combining mutagenesis, NMR spectroscopy, and computational mod ...
Full textLink to itemCite
Journal ArticleJ Am Chem Soc · October 25, 2023
Knowing the 3D structures formed by the various conformations populating the RNA free-energy landscape, their relative abundance, and kinetic interconversion rates is required to obtain a quantitative and predictive understanding of how RNAs fold and funct ...
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Journal ArticleNat Chem Biol · July 2023
Replicative errors contribute to the genetic diversity needed for evolution but in high frequency can lead to genomic instability. Here, we show that DNA dynamics determine the frequency of misincorporating the A•G mismatch, and altered dynamics explain th ...
Full textLink to itemCite
Journal ArticleProc Natl Acad Sci U S A · June 20, 2023
In the mid-1930s, the English mathematician and logician Alan Turing invented an imaginary machine which could emulate the process of manipulating finite symbolic configurations by human computers. His machine launched the field of computer science and pro ...
Full textLink to itemCite
Journal ArticleNature · May 2023
Cellular processes are the product of interactions between biomolecules, which associate to form biologically active complexes1. These interactions are mediated by intermolecular contacts, which if disrupted, lead to alterations in cell physiology. Neverth ...
Full textLink to itemCite
Journal ArticleFrontiers in molecular biosciences · January 2023
Numerous biological processes and mechanisms depend on details of base pairing and hydrogen bonding in DNA. Hydrogen bonds are challenging to quantify by X-ray crystallography and cryo-EM due to difficulty of visualizing hydrogen atom locations but can be ...
Full textCite
Journal ArticleCell Rep · August 30, 2022
N6-methyladenosine (m6A) is deposited co-transcriptionally on thousands of cellular mRNAs and plays important roles in mRNA processing and cellular function. m6A is particularly abundant within the brain and is critical for neurodevelopment. However, the m ...
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Journal ArticleProc Natl Acad Sci U S A · July 26, 2022
The majority of base pairs in double-stranded DNA exist in the canonical Watson-Crick geometry. However, they can also adopt alternate Hoogsteen conformations in various complexes of DNA with proteins and small molecules, which are key for biological funct ...
Full textLink to itemCite
Journal ArticleProc Natl Acad Sci U S A · June 14, 2022
Thermodynamic preferences to form non-native conformations are crucial for understanding how nucleic acids fold and function. However, they are difficult to measure experimentally because this requires accurately determining the population of minor low-abu ...
Full textLink to itemCite
Journal ArticleProc Natl Acad Sci U S A · March 8, 2022
SignificanceUnderstanding and treating neurological disorders are global priorities. Some of these diseases are engendered by mutations that cause defects in the cellular synthesis of transfer RNAs (tRNAs), which function as adapter molecules that translat ...
Full textLink to itemCite
Journal ArticleNucleic Acids Res · December 2, 2021
Watson-Crick base pairs (bps) are the fundamental unit of genetic information and the building blocks of the DNA double helix. However, A-T and G-C can also form alternative 'Hoogsteen' bps, expanding the functional complexity of DNA. We developed 'Hoog-fi ...
Full textLink to itemCite
Journal ArticleCurr Opin Struct Biol · October 2021
Nucleic acids do not fold into a single conformation, and dynamic ensembles are needed to describe their propensities to cycle between different conformations when performing cellular functions. We review recent advances in solution-state nuclear magnetic ...
Full textLink to itemCite
Journal ArticleNat Commun · August 31, 2021
N6-methyladenosine (m6A) is a post-transcriptional modification that controls gene expression by recruiting proteins to RNA sites. The modification also slows biochemical processes through mechanisms that are not understood. Using temperature-dependent (20 ...
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Journal ArticleRNA · January 2021
Identifying small molecules that selectively bind an RNA target while discriminating against all other cellular RNAs is an important challenge in RNA-targeted drug discovery. Much effort has been directed toward identifying drug-like small molecules that m ...
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Journal ArticleMagn Reson (Gott) · 2021
In duplex DNA, Watson-Crick A-T and G-C base pairs (bp's) exist in dynamic equilibrium with an alternative Hoogsteen conformation, which is low in abundance and short-lived. Measuring how the Hoogsteen dynamics varies across different DNA sequences, struct ...
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Journal ArticleNucleic Acids Res · December 2, 2020
2'-O-Methyl (Nm) is a highly abundant post-transcriptional RNA modification that plays important biological roles through mechanisms that are not entirely understood. There is evidence that Nm can alter the biological activities of RNAs by biasing the ribo ...
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Journal ArticleJ Biol Chem · November 20, 2020
As the Watson-Crick faces of nucleobases are protected in dsDNA, it is commonly assumed that deleterious alkylation damage to the Watson-Crick faces of nucleobases predominantly occurs when DNA becomes single-stranded during replication and transcription. ...
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Journal ArticleNat Commun · November 2, 2020
Biomolecules form dynamic ensembles of many inter-converting conformations which are key for understanding how they fold and function. However, determining ensembles is challenging because the information required to specify atomic structures for thousands ...
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Journal ArticleNature · November 2020
Transcription factors recognize specific genomic sequences to regulate complex gene-expression programs. Although it is well-established that transcription factors bind to specific DNA sequences using a combination of base readout and shape recognition, so ...
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Journal ArticleJ Biomol NMR · September 2020
NMR off-resonance R1ρ relaxation dispersion measurements on base carbon and nitrogen nuclei have revealed that wobble G·T/U mismatches in DNA and RNA duplexes exist in dynamic equilibrium with short-lived, low-abundance, and mutagenic Watson-Crick-like con ...
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Journal ArticleAngew Chem Int Ed Engl · July 6, 2020
Biomolecules undergo motions on the micro-to-millisecond timescale to adopt low-populated transient states that play important roles in folding, recognition, and catalysis. NMR techniques, such as Carr-Purcell-Meiboom-Gill (CPMG), chemical exchange saturat ...
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Journal ArticleJ Am Chem Soc · June 24, 2020
DNA bases can adopt energetically unfavorable tautomeric forms that enable the formation of Watson-Crick-like (WC-like) mispairs, which have been proposed to give rise to spontaneous mutations in DNA and misincorporation errors in DNA replication and trans ...
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Journal ArticleBiochemistry · June 16, 2020
Thermostable reverse transcriptases are workhorse enzymes underlying nearly all modern techniques for RNA structure mapping and for the transcriptome-wide discovery of RNA chemical modifications. Despite their wide use, these enzymes' behaviors at chemical ...
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Journal ArticleNat Struct Mol Biol · June 2020
An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...
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Journal ArticleCell Rep · February 25, 2020
Low-abundance short-lived non-native conformations referred to as excited states (ESs) are increasingly observed in vitro and implicated in the folding and biological activities of regulatory RNAs. We developed an approach for assessing the relative abunda ...
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Journal ArticleJ Mol Biol · February 14, 2020
Many promising RNA drug targets have functions that require the formation of RNA-protein complexes, but inhibiting RNA-protein interactions can prove difficult using small molecules. Regulatory RNAs have been shown to transiently form excited conformationa ...
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Journal ArticleJ Am Chem Soc · January 15, 2020
RNA recognition frequently results in conformational changes that optimize intermolecular binding. As a consequence, the overall binding affinity of RNA to its binding partners depends not only on the intermolecular interactions formed in the bound state b ...
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Journal ArticleAdvanced Materials · January 1, 2020
Biomolecules undergo motions on the micro-tomillisecond timescale to adopt low-populated transient states that play important roles in folding, recognition, and catalysis. NMR techniques, such as Carr–Purcell–Meiboom–Gill (CPMG), chemical exchange saturati ...
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Journal ArticleJ Am Chem Soc · December 26, 2019
N6-Methyladenosine (m6A) is an abundant epitranscriptomic modification that plays important roles in many aspects of RNA metabolism. While m6A is thought to mainly function by recruiting reader proteins to specific RNA sites, the modification can also resh ...
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Journal ArticleJ Magn Reson · November 2019
NMR relaxation dispersion studies have shown that Watson-Crick G-C and A-T base pairs in duplex DNA exist in dynamic equilibrium with their Hoogsteen counterparts. Hoogsteen base pairs form through concurrent rotation of the purine base about the glycosidi ...
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Journal ArticleAngew Chem Int Ed Engl · August 26, 2019
Hoogsteen DNA base pairs (bps) are an alternative base pairing to canonical Watson-Crick bps and are thought to play important biochemical roles. Hoogsteen bps have been reported in a handful of X-ray structures of protein-DNA complexes. However, there are ...
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Journal ArticleNat Rev Mol Cell Biol · August 2019
RNAs fold into 3D structures that range from simple helical elements to complex tertiary structures and quaternary ribonucleoprotein assemblies. The functions of many regulatory RNAs depend on how their 3D structure changes in response to a diverse array o ...
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Journal ArticleNucleic Acids Res · July 26, 2019
The HIV-1 Rev response element (RRE) RNA element mediates the nuclear export of intron containing viral RNAs by forming an oligomeric complex with the viral protein Rev. Stem IIB and nearby stem II three-way junction nucleate oligomerization through cooper ...
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Journal ArticleBiochemistry · April 23, 2019
The N-methyltransferase TylM1 from Streptomyces fradiae catalyzes the final step in the biosynthesis of the deoxyamino sugar mycaminose, a substituent of the antibiotic tylosin. The high-resolution crystal structure of TylM1 bound to the methyl donor S-ade ...
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Journal ArticleBiochemistry · April 16, 2019
A( syn)-T and G( syn)-C+ Hoogsteen base pairs in protein-bound DNA duplexes can be difficult to resolve by X-ray crystallography due to ambiguous electron density and by nuclear magnetic resonance (NMR) spectroscopy due to poor chemical shift dispersion an ...
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Journal ArticleNucleic Acids Res · February 28, 2019
Kinetoplastid RNA (kRNA) editing takes place in the mitochondria of kinetoplastid protists and creates translatable mRNAs by uridine insertion/deletion. Extensively edited (pan-edited) transcripts contain quadruplex forming guanine stretches, which must be ...
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Journal ArticleProg Nucl Magn Reson Spectrosc · 2019
This review describes off-resonance R1ρ relaxation dispersion NMR methods for characterizing microsecond-to-millisecond chemical exchange in uniformly 13C/15N labeled nucleic acids in solution. The review opens with a historical account of key developments ...
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Journal ArticlePLoS One · 2019
N6-methyladenosine (m6A) is a ubiquitous RNA post-transcriptional modification found in coding as well as non-coding RNAs. m6A has also been found in viral RNAs where it is proposed to modulate host-pathogen interactions. Two m6A sites have been reported i ...
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Journal ArticleChemistry · December 17, 2018
Watson-Crick like G-U mismatches with tautomeric Genol or Uenol bases can evade fidelity checkpoints and thereby contribute to translational errors. The 5-oxyacetic acid uridine (cmo5 U) modification is a base modification at the wobble position on tRNAs a ...
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Journal ArticleNucleic Acids Res · November 16, 2018
A(syn)-U/T and G(syn)-C+ Hoogsteen (HG) base pairs (bps) are energetically more disfavored relative to Watson-Crick (WC) bps in A-RNA as compared to B-DNA by >1 kcal/mol for reasons that are not fully understood. Here, we used NMR spectroscopy, optical mel ...
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Journal ArticleRNA · October 2018
Helical elements separated by bulges frequently undergo transitions between unstacked and coaxially stacked conformations during the folding and function of noncoding RNAs. Here, we examine the dynamic properties of poly-pyrimidine bulges of varying length ...
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Journal ArticleNat Commun · July 17, 2018
N6-Methyladenosine (m6A) is an abundant post-transcriptional RNA modification that influences multiple aspects of gene expression. In addition to recruiting proteins, m6A can modulate RNA function by destabilizing base pairing. Here, we show that when neig ...
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Journal ArticleBiochemistry · July 3, 2018
The C-terminal domain of cobalamin-dependent methionine synthase (MetH) has an essential role in catalyzing the reactivation of the enzyme following the oxidation of its cobalamin cofactor. This reactivation occurs through reductive methylation of the coba ...
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Journal ArticleNat Struct Mol Biol · May 2018
Dynamic ensembles hold great promise in advancing RNA-targeted drug discovery. Here we subjected the transactivation response element (TAR) RNA from human immunodeficiency virus type-1 to experimental high-throughput screening against ~100,000 drug-like sm ...
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Journal ArticleNat Commun · April 16, 2018
In naked duplex DNA, G-C and A-T Watson-Crick base pairs exist in dynamic equilibrium with their Hoogsteen counterparts. Here, we used nuclear magnetic resonance (NMR) relaxation dispersion and molecular dynamics (MD) simulations to examine how Watson-Cric ...
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Journal ArticleJ Biomol NMR · April 2018
NMR relaxation dispersion studies indicate that in canonical duplex DNA, Watson-Crick base pairs (bps) exist in dynamic equilibrium with short-lived low abundance excited state Hoogsteen bps. N1-methylated adenine (m1A) and guanine (m1G) are naturally occu ...
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Journal ArticleCell Rep · March 20, 2018
Large-scale, cooperative rearrangements underlie the functions of RNA in RNA-protein machines and gene regulation. To understand how such rearrangements are orchestrated, we used high-throughput chemical footprinting to dissect a seemingly concerted rearra ...
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Journal ArticleNature · February 8, 2018
Tautomeric and anionic Watson-Crick-like mismatches have important roles in replication and translation errors through mechanisms that are not fully understood. Here, using NMR relaxation dispersion, we resolve a sequence-dependent kinetic network connecti ...
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Journal ArticleJ Mol Biol · January 5, 2018
HdeA is a periplasmic chaperone that is rapidly activated upon shifting the pH to acidic conditions. This activation is thought to involve monomerization of HdeA. There is evidence that monomerization and partial unfolding allow the chaperone to bind to pr ...
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Journal ArticleNucleic Acids Res · August 21, 2017
Recent studies have shown that RNAs exist in dynamic equilibrium with short-lived low-abundance 'excited states' that form by reshuffling base pairs in and around non-canonical motifs. These conformational states are proposed to be rich in non-canonical mo ...
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Journal ArticleFEBS Lett · June 2017
Noncanonical G-C+ and A-T Hoogsteen base pairs can form in duplex DNA and play roles in recognition, damage repair, and replication. Identifying Hoogsteen base pairs in DNA duplexes remains challenging due to difficulties in resolving syn versus antipurine ...
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Journal ArticleNucleic Acids Res · May 19, 2017
In the canonical DNA double helix, Watson-Crick (WC) base pairs (bps) exist in dynamic equilibrium with sparsely populated (∼0.02-0.4%) and short-lived (lifetimes ∼0.2-2.5 ms) Hoogsteen (HG) bps. To gain insights into transient HG bps, we used solution-sta ...
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Journal ArticleRNA · May 2017
RNA modifications are ubiquitous in biology, with over 100 distinct modifications. While the vast majority were identified and characterized on abundant noncoding RNA such as tRNA and rRNA, the advent of sensitive sequencing-based approaches has led to the ...
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Journal ArticleMedchemcomm · May 1, 2017
Diversification of RNA-targeted scaffolds offers great promise in the search for selective ligands of therapeutically relevant RNA such as HIV-1 TAR. We herein report the establishment of amiloride as a novel RNA-binding scaffold along with synthetic route ...
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Journal ArticleJ Am Chem Soc · March 29, 2017
The replicative and translational machinery utilizes the unique geometry of canonical G·C and A·T/U Watson-Crick base pairs to discriminate against DNA and RNA mismatches in order to ensure high fidelity replication, transcription, and translation. There i ...
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Journal ArticleACS Macro Lett · October 18, 2016
Prototropic and solvatochromatic properties of fluorescein (FL) were employed to detect the presence of microenvironments in polyplexes consisting of polycationic polymer (POCP) and a fluorescein-conjugated RNA, the HIV-1 transactivation response element ( ...
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Journal ArticleJ Mol Biol · October 9, 2016
Structured RNAs fold through multiple pathways, but we have little understanding of the molecular features that dictate folding pathways and determine rates along a given pathway. Here, we asked whether folding of a complex RNA can be understood from its s ...
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Journal ArticleNat Struct Mol Biol · September 2016
The B-DNA double helix can dynamically accommodate G-C and A-T base pairs in either Watson-Crick or Hoogsteen configurations. Here, we show that G-C(+) (in which + indicates protonation) and A-U Hoogsteen base pairs are strongly disfavored in A-RNA. As a r ...
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Journal ArticleBiochemistry · August 16, 2016
Helix-junction-helix (HJH) motifs are flexible building blocks of RNA architecture that help define the orientation and dynamics of helical domains. They are also frequently involved in adaptive recognition of proteins and small molecules and in the format ...
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Journal ArticleNat Commun · June 13, 2016
Intermediates play important roles in RNA folding but can be difficult to characterize when short-lived or not significantly populated. By combining (15)N relaxation dispersion NMR with chemical probing, we visualized a fast (kex=k1+k-1≈423 s(-1)) secondar ...
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Journal ArticlePhys Chem Chem Phys · February 17, 2016
Detecting conformational heterogeneity in biological macromolecules is a key for the understanding of their biological function. We here provide a comparison between two independent approaches to assess conformational heterogeneity: molecular dynamics simu ...
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Journal ArticleBiomacromolecules · January 11, 2016
A combination of solution NMR, dynamic light scattering (DLS), and fluorescence quenching assays were employed to obtain insights into the dynamics and structural features of a polyplex system consisting of HIV-1 transactivation response element (TAR) and ...
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Journal ArticleNucleic Acids Res · January 8, 2016
A requirement for specific RNA folding is that the free-energy landscape discriminate against non-native folds. While tertiary interactions are critical for stabilizing the native fold, they are relatively non-specific, suggesting additional mechanisms con ...
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Journal ArticleCell Rep · December 1, 2015
Naturally occurring L-glutamine riboswitches occur in cyanobacteria and marine metagenomes, where they reside upstream of genes involved in nitrogen metabolism. By combining X-ray, NMR, and MD, we characterized an L-glutamine-dependent conformational trans ...
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Journal ArticleCell · October 22, 2015
A key effector route of the Sugar Code involves lectins that exert crucial regulatory controls by targeting distinct cellular glycans. We demonstrate that a single amino-acid substitution in a banana lectin, replacing histidine 84 with a threonine, signifi ...
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Journal ArticleJ Am Chem Soc · October 14, 2015
Approaches that combine experimental data and computational molecular dynamics (MD) to determine atomic resolution ensembles of biomolecules require the measurement of abundant experimental data. NMR residual dipolar couplings (RDCs) carry rich dynamics in ...
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Journal ArticleJ Phys Chem B · July 30, 2015
A growing number of studies employ time-averaged experimental data to determine dynamic ensembles of biomolecules. While it is well-known that different ensembles can satisfy experimental data to within error, the extent and nature of these degeneracies, a ...
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Journal ArticleBiophys J · June 16, 2015
RNA function depends crucially on the details of its dynamics. The simplest RNA dynamical unit is a two-way interhelical junction. Here, for such a unit--the transactivation response RNA element--we present evidence from molecular dynamics simulations, sup ...
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Journal ArticleNucleic Acids Res · April 20, 2015
Hoogsteen (HG) base pairs (bps) provide an alternative pairing geometry to Watson-Crick (WC) bps and can play unique functional roles in duplex DNA. Here, we use structural features unique to HG bps (syn purine base, HG hydrogen bonds and constricted C1'-C ...
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Journal ArticleNature · March 19, 2015
Rare tautomeric and anionic nucleobases are believed to have fundamental biological roles, but their prevalence and functional importance has remained elusive because they exist transiently, in low abundance, and involve subtle movements of protons that ar ...
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Journal ArticleJ Am Chem Soc · March 18, 2015
Mammalian mitochondrial tRNA(Ser(UCN)) (mt-tRNA(Ser)) and pyrrolysine tRNA (tRNA(Pyl)) fold to near-canonical three-dimensional structures despite having noncanonical secondary structures with shortened interhelical loops that disrupt the conserved tRNA te ...
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Journal ArticleBiophys J · February 3, 2015
The HIV-1 frameshift site (FS) plays a critical role in viral replication. During translation, the HIV-1 FS transitions from a 3-helix to a 2-helix junction RNA secondary structure. The 2-helix junction structure contains a GGA bulge, and purine-rich bulge ...
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Journal ArticleMethods Enzymol · 2015
Changes in RNA secondary structure play fundamental roles in the cellular functions of a growing number of noncoding RNAs. This chapter describes NMR-based approaches for characterizing microsecond-to-millisecond changes in RNA secondary structure that are ...
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Journal ArticleBiochemistry · November 25, 2014
We recently showed that Watson-Crick base pairs in canonical duplex DNA exist in dynamic equilibrium with G(syn)·C+ and A(syn)·T Hoogsteen base pairs that have minute populations of ∼1%. Here, using nuclear magnetic resonance R1ρ relaxation dispersion, we ...
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Journal ArticleJ Biomol NMR · November 2014
Higher sensitivity of NMR spectrometers and novel isotopic labeling schemes have ushered the development of rapid data acquisition methodologies, improving the time resolution with which NMR data can be acquired. For nucleic acids, longitudinal relaxation ...
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Journal ArticleAcc Chem Res · October 21, 2014
Many multidomain proteins and ribonucleic acids consist of domains that autonomously fold and that are linked together by flexible junctions. This architectural design allows domains to sample a wide range of positions with respect to one another, yet do s ...
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Journal ArticleNucleic Acids Res · October 2014
Recent studies have shown that basic steric and connectivity constraints encoded at the secondary structure level are key determinants of 3D structure and dynamics in simple two-way RNA junctions. However, the role of these topological constraints in highe ...
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Journal ArticleJ Mol Biol · September 23, 2014
Ribosomes control the missense error rate of ~10(-4) during translation though quantitative contributions of individual mechanistic steps of the conformational changes yet to be fully determined. Biochemical and biophysical studies led to a qualitative tRN ...
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Journal ArticleNat Commun · September 4, 2014
Hoogsteen (HG) base pairing involves a 180° rotation of the purine base relative to Watson-Crick (WC) base pairing within DNA duplexes, creating alternative DNA conformations that can play roles in recognition, damage induction and replication. Here, using ...
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Journal ArticleACS Chem Biol · August 15, 2014
Recent studies have demonstrated that the active sites of S-adenosylmethionine (AdoMet)-dependent methyltransferases form strong carbon-oxygen (CH···O) hydrogen bonds with the substrate's sulfonium group that are important in AdoMet binding and catalysis. ...
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Journal ArticleGenome Biol · July 30, 2014
A viral tRNA-like structure has evolved a unique strategy to undergo a tertiary structure conformational switch that may help regulate viral regulation. ...
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Journal ArticleProc Natl Acad Sci U S A · July 1, 2014
Using on- and off-resonance carbon and nitrogen R1ρ NMR relaxation dispersion in concert with mutagenesis and NMR chemical shift fingerprinting, we show that the transactivation response element RNA from the HIV-1 exists in dynamic equilibrium with a trans ...
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Journal ArticleJ Magn Reson · July 2014
Spin relaxation in the rotating frame (R1ρ) is a powerful NMR technique for characterizing fast microsecond timescale exchange processes directed toward short-lived excited states in biomolecules. At the limit of fast exchange, only k(ex)=k(1)+k(-1) and Φe ...
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Journal ArticleRNA · June 2014
Many regulatory RNAs contain long single strands (ssRNA) that adjoin secondary structural elements. Here, we use NMR spectroscopy to study the dynamic properties of a 12-nucleotide (nt) ssRNA tail derived from the prequeuosine riboswitch linked to the 3' e ...
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Journal ArticleNat Methods · May 2014
We present a simple and general approach termed REsemble for quantifying population overlap and structural similarity between ensembles. This approach captures improvements in the quality of ensembles determined using increasing input experimental data--im ...
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Journal ArticleJ Phys Chem B · March 13, 2014
Recent studies have shown that simple stereochemical constraints encoded at the RNA secondary structure level significantly restrict the orientation of RNA helices across two-way junctions and yield physically reasonable distributions of RNA 3D conformatio ...
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Journal ArticleCurr Opin Struct Biol · February 2014
There are a growing number of studies reporting the observation of purine-pyrimidine base-pairs that are seldom observed in unmodified nucleic acids because they entail the loss of energetically favorable interactions or require energetically costly base i ...
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Journal ArticleAnnu Rev Biochem · 2014
RNA dynamics play a fundamental role in many cellular functions. However, there is no general framework to describe these complex processes, which typically consist of many structural maneuvers that occur over timescales ranging from picoseconds to seconds ...
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Journal ArticleAnnu Rev Phys Chem · 2014
Conformational changes in nucleic acids play a key role in the way genetic information is stored, transferred, and processed in living cells. Here, we describe new approaches that employ a broad range of experimental data, including NMR-derived chemical sh ...
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Journal ArticleJ Magn Reson · December 2013
Nucleic acid structures have to satisfy two diametrically opposite requirements; on one hand they have to adopt well-defined 3D structures that can be specifically recognized by proteins; on the other hand, their structures must be sufficiently flexible to ...
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Journal ArticleNucleic Acids Res · December 2013
Riboswitches are structural elements in the 5' untranslated regions of many bacterial messenger RNAs that regulate gene expression in response to changing metabolite concentrations by inhibition of either transcription or translation initiation. The preQ1 ...
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Journal ArticleBiopolymers · December 2013
In 1957, a unique pattern of hydrogen bonding between N3 and O4 on uracil and N7 and N6 on adenine was proposed to explain how poly(rU) strands can associate with poly(rA)-poly(rU) duplexes to form triplexes. Two years later, Karst Hoogsteen visualized suc ...
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Journal ArticleJ Am Chem Soc · October 16, 2013
S-adenosylmethionine (AdoMet)-based methylation is integral to metabolism and signaling. AdoMet-dependent methyltransferases belong to multiple distinct classes and share a catalytic mechanism that arose through convergent evolution; however, fundamental d ...
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Journal ArticleAnal Chem · October 15, 2013
Dimethyl sulfoxide (DMSO) is widely used as a cosolvent to solubilize hydrophobic compounds in RNA-ligand binding assays. Although it is known that high concentrations of DMSO (>75%) can significantly affect RNA structure and folding energetics, a thorough ...
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Journal ArticleJ Am Chem Soc · May 8, 2013
G·C Hoogsteen base pairs can form transiently in duplex DNA and play important roles in DNA recognition, replication, and repair. G·C Hoogsteen base pairs are thought to be stabilized by protonation of cytosine N3, which affords a second key hydrogen bond, ...
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Journal ArticleJ Am Chem Soc · April 10, 2013
The ability to modulate alignment and measure multiple independent sets of NMR residual dipolar couplings (RDCs) has made it possible to characterize internal motions in proteins at atomic resolution and with time scale sensitivity ranging from picoseconds ...
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Journal ArticleJ Phys Chem B · February 21, 2013
The development of methods for predicting NMR chemical shifts with high accuracy and speed is increasingly allowing use of these abundant, readily accessible measurements in determining the structure and dynamics of proteins. For nucleic acids, however, de ...
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Journal ArticleNature · November 29, 2012
The visualization of RNA conformational changes has provided fundamental insights into how regulatory RNAs carry out their biological functions. The RNA structural transitions that have been characterized so far involve long-lived species that can be captu ...
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Journal ArticleBiochemistry · October 30, 2012
Sequence-specific DNA flexibility plays a key role in a variety of cellular interactions that are critical for gene packaging, expression, and regulation, yet few studies have experimentally explored the sequence dependence of DNA dynamics that occur on bi ...
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Journal ArticleMol Pharm · September 4, 2012
The transfer of genetic material into cells using nonviral vectors offers unique potential for therapeutics; however, the efficacy of delivery depends upon a poorly understood, multistep pathway, limiting the prospects for successful gene delivery. Mechani ...
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Journal ArticleBiochemistry · August 28, 2012
The left-handed DNA structure, Z-DNA, is believed to play important roles in gene expression and regulation. Z-DNA forms sequence-specifically with a preference for sequences rich in pyrimidine/purine dinucleotide steps. In vivo, Z-DNA is generated in the ...
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Journal ArticleJ Am Chem Soc · February 29, 2012
Nucleic acids transiently morph into alternative conformations that can be difficult to characterize at the atomic level by conventional methods because they exist for too little time and in too little abundance. We recently reported evidence for transient ...
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Journal ArticleNature · February 15, 2012
Changes to the conformation of coding and non-coding RNAs form the basis of elements of genetic regulation and provide an important source of complexity, which drives many of the fundamental processes of life. Although the structure of RNA is highly flexib ...
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Journal ArticleNucleic Acids Res · February 2012
Single-stranded RNAs (ssRNAs) are ubiquitous RNA elements that serve diverse functional roles. Much of our understanding of ssRNA conformational behavior is limited to structures in which ssRNA directly engages in tertiary interactions or is recognized by ...
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Journal ArticleNucleic Acids Res · January 2012
Recent studies have shown that topological constraints encoded at the RNA secondary structure level involving basic steric and stereochemical forces can significantly restrict the orientations sampled by helices across two-way RNA junctions. Here, we formu ...
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Journal ArticleNat Methods · October 28, 2011
Many recently discovered noncoding RNAs do not fold into a single native conformation but sample many different conformations along their free-energy landscape to carry out their biological function. Here we review solution-state NMR techniques that measur ...
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Journal ArticleNat Protoc · September 15, 2011
More than 50% of RNA secondary structure is estimated to be A-form helices, which are linked together by various junctions. Here we describe a protocol for computing three interhelical Euler angles describing the relative orientation of helices across RNA ...
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Journal ArticleBiochemistry · July 12, 2011
The antimicrobial peptide MSI-78 serves as a model system for studying interactions of bioactive peptides with membranes. Using a series of MSI-78 peptides that incorporate l-4,4,4-trifluoroethylglycine, a small and sensitive (19)F nuclear magnetic resonan ...
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Journal ArticleNat Chem Biol · June 26, 2011
Current approaches used to identify protein-binding small molecules are not suited for identifying small molecules that can bind emerging RNA drug targets. By docking small molecules onto an RNA dynamic ensemble constructed by combining NMR spectroscopy an ...
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Journal ArticleCurr Opin Struct Biol · June 2011
Accompanying recent advances in determining RNA secondary structure is the growing appreciation for the importance of relatively simple topological constraints, encoded at the secondary structure level, in defining the overall architecture, folding pathway ...
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Journal ArticleJ Biol Chem · May 27, 2011
SET domain lysine methyltransferases (KMTs) are S-adenosylmethionine (AdoMet)-dependent enzymes that catalyze the site-specific methylation of lysyl residues in histone and non-histone proteins. Based on crystallographic and cofactor binding studies, carbo ...
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Journal ArticleNature · February 24, 2011
Sequence-directed variations in the canonical DNA double helix structure that retain Watson-Crick base-pairing have important roles in DNA recognition, topology and nucleosome positioning. By using nuclear magnetic resonance relaxation dispersion spectrosc ...
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Journal ArticleJ Am Chem Soc · February 23, 2011
Conversion of right-handed B-DNA into left-handed Z-DNA is one of the largest structural transitions in biology that plays fundamental roles in gene expression and regulation. Z-DNA segments must form within genomes surrounded by a sea of B-DNA and require ...
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Journal ArticleRNA · September 2010
The melting of base pairs is a ubiquitous feature of RNA structural transitions, which are widely used to sense and respond to cellular stimuli. A recent study employing solution nuclear magnetic resonance (NMR) imino proton exchange spectroscopy provides ...
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Journal ArticleBiochemistry · July 13, 2010
A variety of biologically active peptides exert their function through direct interactions with the lipid membrane of the cell. These surface interactions are generally transient and highly dynamic, making them hard to study. Here we have examined the feas ...
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Journal ArticleProc Natl Acad Sci U S A · February 9, 2010
Functionally critical metals interact with RNA through complex coordination schemes that are currently difficult to visualize at the atomic level under solution conditions. Here, we report a new approach that combines NMR and XAS to resolve and characteriz ...
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Journal ArticleJ Phys Chem B · January 21, 2010
Nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations are both techniques that can be used to characterize the structural dynamics of biomolecules and their underlying time scales. Comparison of relaxation parameters obtaine ...
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Journal ArticleScience · January 8, 2010
Thermodynamic rules that link RNA sequences to secondary structure are well established, but the link between secondary structure and three-dimensional global conformation remains poorly understood. We constructed comprehensive three-dimensional maps depic ...
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Journal ArticleJ Magn Reson · January 2010
The application of residual dipolar couplings (RDCs) in studies of RNA structure and dynamics can be complicated by the presence of couplings between collective helix motions and overall alignment and by the inability to modulate overall alignment of the m ...
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Journal ArticleBiopolymers · January 2010
Bz-423 is an inhibitor of the mitochondrial F(1)F(0)-ATPase, with therapeutic properties in murine models of immune diseases. Here, we study the binding of a water-soluble Bz-423 analog (5-(3-(aminomethyl)phenyl)-7-chloro- 1-methyl-3-(naphthalen-2-ylmethyl ...
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Journal ArticleBiochemistry · November 17, 2009
The incorporation of extensively fluorinated, or fluorous, analogues of hydrophobic amino acids into proteins potentially provides the opportunity to modulate the physicochemical properties of proteins in a predictable manner. On the basis of the propertie ...
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Journal ArticleRNA · November 2009
By simplifying the interpretation of nuclear magnetic resonance spin relaxation and residual dipolar couplings data, recent developments involving the elongation of RNA helices are providing new atomic insights into the dynamical properties that allow RNA ...
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Journal ArticleMethods · October 2009
A broad structural landscape often needs to be characterized in order to fully understand how regulatory RNAs perform their biological functions at the atomic level. We present a protocol for visualizing thermally accessible RNA conformations at atomic-res ...
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Journal ArticleJ Biomol NMR · September 2009
DNA is a highly flexible molecule that undergoes functionally important structural transitions in response to external cellular stimuli. Atomic level spin relaxation NMR studies of DNA dynamics have been limited to short duplexes in which sensitivity to bi ...
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Journal ArticleNucleic Acids Res · June 2009
We describe a strategy for constructing atomic resolution dynamical ensembles of RNA molecules, spanning up to millisecond timescales, that combines molecular dynamics (MD) simulations with NMR residual dipolar couplings (RDC) measured in elongated RNA. Th ...
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Journal ArticleACS Chem Biol · May 15, 2009
Small molecules that reconstitute the binding mode(s) of a protein and in doing so elicit a programmed functional response offer considerable advantages in the control of complex biological processes. The development challenges of such molecules are signif ...
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Journal ArticleJ Phys Chem B · May 7, 2009
NMR spectroscopy is one of the most powerful techniques for studying the internal dynamics of biomolecules. Current formalisms approximate the dynamics using simple continuous motional models or models involving discrete jumps between a small number of sta ...
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Journal ArticleJ Am Chem Soc · March 25, 2009
We present an off-resonance carbon R(1rho) NMR experiment utilizing weak radiofrequency fields and selective polarization transfers for quantifying chemical-exchange processes in nucleic acids. The experiment extends the range of accessible time scales to ...
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Journal ArticleJ Phys Chem B · December 25, 2008
Nuclear magnetic resonance (NMR) residual dipolar couplings (RDCs) provide a unique opportunity for spatially characterizing complex motions in biomolecules with time scale sensitivity extending up to milliseconds. Up to five motionally averaged Wigner rot ...
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Journal ArticleBiophys J · October 2008
The HIV-1 transactivation response element (TAR) RNA binds a variety of proteins and is a target for developing anti-HIV therapies. TAR has two primary binding sites: a UCU bulge and a CUGGGA apical loop. We used NMR residual dipolar couplings, carbon spin ...
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Journal ArticleCurr Opin Struct Biol · June 2008
Many recently discovered RNA functions rely on highly complex multistep conformational transitions that occur in response to an array of cellular signals. These dynamics accompany and guide, for example, RNA cotranscriptional folding, ligand sensing and si ...
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Journal ArticleNat Methods · March 2008
Experimental resolution of distinct dynamical processes in molecules can prove impossible when they are correlated to one another. In nuclear magnetic resonance (NMR) spectroscopy, couplings between internal and overall motions lead to intractable complexi ...
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Journal ArticleJ Am Chem Soc · December 26, 2007
We present an NMR strategy for characterizing picosecond-to-nanosecond internal motions in uniformly 13C/15N-labeled RNAs that combines measurements of R1, R1rho, and heteronuclear 13C{1H} NOEs for protonated base (C2, C5, C6, and C8) and sugar (C1') carbo ...
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Journal ArticleNature · December 20, 2007
RNAs fold into three-dimensional (3D) structures that subsequently undergo large, functionally important, conformational transitions in response to a variety of cellular signals. RNA structures are believed to encode spatially tuned flexibility that can di ...
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Journal ArticleBiopolymers · August 5, 2007
An increasing number of RNAs are being discovered that perform their functions by undergoing large changes in conformation in response to a variety of cellular signals, including recognition of proteins and small molecular targets, changes in temperature, ...
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Journal ArticleBiophys J · July 15, 2007
The HIV-1 transactivation response RNA element (TAR), which is essential to the lifecycle of the virus, has been suggested, based on NMR and hydrodynamic measurements, to undergo substantial, collective, structural dynamics that are important for its funct ...
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Journal ArticleBiochemistry · June 5, 2007
Many regulatory RNAs undergo large changes in structure upon recognition of proteins and ligands, but the mechanism by which this occurs remains poorly understood. Using NMR residual dipolar coupling (RDCs), we characterized Na+-induced changes in the stru ...
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Journal ArticleRNA · February 2007
The P4 helix is an essential element of ribonuclease P (RNase P) that is believed to bind catalytically important metals. Here, we applied a combination of NMR residual dipolar couplings (RDCs) and a recently introduced domain-elongation strategy for measu ...
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Journal ArticleNat Protoc · 2007
We present a protocol for determining the relative orientation and dynamics of A-form helices in 13C/15N isotopically enriched RNA samples using NMR residual dipolar couplings (RDCs). Non-terminal Watson-Crick base pairs in helical stems are experimentally ...
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Journal ArticleNucleic Acids Res · 2007
Stem loop 1 (SL1) is a highly conserved hairpin in the 5'-leader of the human immunodeficiency virus type I that forms a metastable kissing dimer that is converted during viral maturation into a stable duplex with the aid of the nucleocapsid (NC) protein. ...
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Journal ArticleJ Biomol NMR · December 2006
We examined how static and dynamic deviations from the idealized A-form helix propagate into errors in the principal order tensor parameters determined using residual dipolar couplings (rdcs). A 20-ns molecular dynamics (MD) simulation of the HIV-1 transac ...
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Journal ArticleJ Magn Reson · April 2006
Using residual chemical shift anisotropies (RCSAs) measured in a weakly aligned stem-loop RNA, we examined the carbon chemical shift anisotropy (CSA) tensors of nucleobase adenine C2, pyrimidine C5 and C6, and purine C8. The differences between the measure ...
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Journal ArticleScience · February 3, 2006
Using a domain elongation strategy, we decoupled internal motions in RNA from overall rotational diffusion. This allowed us to site-specifically resolve a manifold of motional modes in two regulatory RNAs from HIV-1 with the use of nuclear magnetic resonan ...
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Journal ArticleJ Am Chem Soc · January 11, 2006
There has recently been much interest in exploiting the unusual properties associated with fluorocarbons to modulate the physicochemical properties of proteins. Here we present a detailed investigation into the effect on structure and stability of systemat ...
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Journal ArticleChembiochem · September 2005
The ever-increasing cellular roles ascribed to RNA raise fundamental questions regarding how a biopolymer composed of only four chemically similar building-block nucleotides achieves such functional diversity. Here, I discuss how RNA achieves added mechani ...
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Journal ArticleJ Mol Biol · April 16, 2004
The structure and dynamics of the stem-loop transactivation response element (TAR) RNA from the human immunodeficiency virus type-1 (HIV-1) bound to the ligand argininamide (ARG) has been characterized using a combination of a large number of residual dipo ...
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Journal ArticleJ Am Chem Soc · September 3, 2003
Approaches developed thus for extracting structural and dynamical information from RDCs have rested on the assumption that motions do not affect molecular alignment. However, it is well established that molecular alignment in ordered media is dependent on ...
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Journal ArticleJ Mol Biol · June 20, 2003
The effects of divalent Mg(2+) on the conformation and dynamics of the stem-loop transactivation response element (TAR) RNA from HIV-1 have been characterized using NMR residual dipolar couplings (RDCs). Order matrix analysis of one bond 13C-1H RDCs measur ...
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Journal ArticleAnnual Reports on NMR Spectroscopy · 2003
Due to their exquisite sensitivity to bond vector orientations and distances, residual dipolar couplings are emerging as a powerful NMR methodology for probing the conformational dynamics of biomolecules. The global organization of multi-domain proteins an ...
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Journal ArticleJ Mol Biol · May 3, 2002
We report a new residual dipolar couplings (RDCs) based NMR procedure for rapidly determining RNA tertiary structure demonstrated on a uniformly (15)N/(13)C-labeled 27 nt variant of the trans-activation response element (TAR) RNA from HIV-I. In this proced ...
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Journal ArticleJ Mol Biol · January 11, 2002
Ground-state dynamics in RNA is a critical precursor for structural adaptation observed ubiquitously in protein-RNA recognition. A tertiary conformational analysis of the stem-loop structural element in the transactivation response element (TAR) from human ...
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Journal ArticleOMICS · 2002
The U.S. Department of Energy recently announced the first five grants for the Genomes to Life (GTL) Program. The goal of this program is to "achieve the most far-reaching of all biological goals: a fundamental, comprehensive, and systematic understanding ...
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Journal ArticleJ Biomol NMR · January 2002
Structural genomics is on a quest for the structure and function of a significant fraction of gene products. Current efforts are focusing on structure determination of single-domain proteins, which can readily be targeted by X-ray crystallography, NMR spec ...
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Journal ArticleJ Am Chem Soc · February 21, 2001
The measurement of residual dipolar couplings in weakly aligned proteins can potentially provide unique information on their structure and dynamics in the solution state. The challenge is to extract the information of interest from the measurements, which ...
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Journal ArticleJ Am Chem Soc · January 31, 2001
We present a new NMR procedure for determining the three-dimensional fold of C2-symmetric nucleic acid homodimers that relies on long-range orientational constraints derived from the measurement of two independent sets of residual dipolar couplings under t ...
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Journal ArticleJ Am Chem Soc · January 24, 2001
We present a new approach to the analysis of the conformational and the motional properties of an oligosaccharide, methyl 3,6-di-O-(alpha-D-mannopyranosyl)-alpha-D-mannopyranoside. The approach relies on an order matrix analysis of residual dipolar couplin ...
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Journal ArticleJ Mol Biol · December 1, 2000
Over the next few years, various genome projects will sequence many new genes and yield many new gene products. Many of these products will have no known function and little, if any, sequence homology to existing proteins. There is reason to believe that a ...
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Journal ArticleJ Magn Reson · April 2000
Residual dipolar couplings for pairs of proximate magnetic nuclei in macromolecules can easily be measured using high-resolution NMR methods when the molecules are dissolved in dilute liquid crystalline media. The resulting couplings can in principle be us ...
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Journal ArticleJ Magn Reson · January 2000
Dipole-dipole couplings between pairs of spin 12 nuclei, which can be measured from NMR spectra in field-ordered media, offer useful constraints on the orientation of various fragments in molecular systems. However, the orientation of fragments relative to ...
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Journal ArticleJ Mol Biol · October 15, 1999
The geometric relationships between ligands and the functional groups that bind ligands in soluble ligand-protein complexes have traditionally been deduced from distance constraints between pairs of NMR active nuclei spanning the ligand-protein interface. ...
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