Skip to main content
Journal cover image

Exploiting a Mechanical Perturbation of a Titin Domain to Identify How Force Field Parameterization Affects Protein Refolding Pathways.

Publication ,  Journal Article
Wang, D; Marszalek, PE
Published in: Journal of chemical theory and computation
May 2020

Molecular mechanics force fields have been shown to differ in their predictions of biomolecular processes such as protein folding. To test how force field differences affect predicted polypeptide behavior, we created a mechanically perturbed model of the β-stranded I91 titin domain based on atomic force spectroscopy data and examined its refolding behavior using six different force fields. We found that different force fields varied significantly in their ability to refold the mechanically perturbed I91 domain. Examination of the perturbed I91 unfolded state revealed that all five Amber force fields oversample a specific region of the Ramachandran plot, thereby creating unfolded state intermediates which are not predicted by the Charmm 22* force field. Simulations of perturbed I91 refolding with Amber FB15 revealed that Amber FB15 destabilizes stable portions of I91, thereby contradicting experimental stability analyses. Finally, inspection of the perturbed I91 unfolded state along with equilibration simulations of the Ac-(AAQAA)3-NH2 peptide suggest that high dihedral torsional barriers cause the Amber ff14SB force field to predict higher helical lifetimes relative to other force fields. These results suggest that using mechanically perturbed models can provide a controlled method to gain insights into how force fields affect polypeptide behavior.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Journal of chemical theory and computation

DOI

EISSN

1549-9626

ISSN

1549-9618

Publication Date

May 2020

Volume

16

Issue

5

Start / End Page

3240 / 3252

Related Subject Headings

  • Protein Structure, Secondary
  • Protein Refolding
  • Humans
  • Connectin
  • Chemical Physics
  • Biomechanical Phenomena
  • 3407 Theoretical and computational chemistry
  • 3406 Physical chemistry
  • 0803 Computer Software
  • 0601 Biochemistry and Cell Biology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wang, D., & Marszalek, P. E. (2020). Exploiting a Mechanical Perturbation of a Titin Domain to Identify How Force Field Parameterization Affects Protein Refolding Pathways. Journal of Chemical Theory and Computation, 16(5), 3240–3252. https://doi.org/10.1021/acs.jctc.0c00080
Wang, David, and Piotr E. Marszalek. “Exploiting a Mechanical Perturbation of a Titin Domain to Identify How Force Field Parameterization Affects Protein Refolding Pathways.Journal of Chemical Theory and Computation 16, no. 5 (May 2020): 3240–52. https://doi.org/10.1021/acs.jctc.0c00080.
Wang D, Marszalek PE. Exploiting a Mechanical Perturbation of a Titin Domain to Identify How Force Field Parameterization Affects Protein Refolding Pathways. Journal of chemical theory and computation. 2020 May;16(5):3240–52.
Wang, David, and Piotr E. Marszalek. “Exploiting a Mechanical Perturbation of a Titin Domain to Identify How Force Field Parameterization Affects Protein Refolding Pathways.Journal of Chemical Theory and Computation, vol. 16, no. 5, May 2020, pp. 3240–52. Epmc, doi:10.1021/acs.jctc.0c00080.
Wang D, Marszalek PE. Exploiting a Mechanical Perturbation of a Titin Domain to Identify How Force Field Parameterization Affects Protein Refolding Pathways. Journal of chemical theory and computation. 2020 May;16(5):3240–3252.
Journal cover image

Published In

Journal of chemical theory and computation

DOI

EISSN

1549-9626

ISSN

1549-9618

Publication Date

May 2020

Volume

16

Issue

5

Start / End Page

3240 / 3252

Related Subject Headings

  • Protein Structure, Secondary
  • Protein Refolding
  • Humans
  • Connectin
  • Chemical Physics
  • Biomechanical Phenomena
  • 3407 Theoretical and computational chemistry
  • 3406 Physical chemistry
  • 0803 Computer Software
  • 0601 Biochemistry and Cell Biology