Constructing atomic structural models into cryo-EM densities using molecular dynamics - Pros and cons.

Journal Article (Journal Article)

Accurate structure determination from electron density maps at 3-5 Å resolution necessitates a balance between extensive global and local sampling of atomistic models, yet with the stereochemical correctness of backbone and sidechain geometries. Molecular Dynamics Flexible Fitting (MDFF), particularly through a resolution-exchange scheme, ReMDFF, provides a robust way of achieving this balance for hybrid structure determination. Employing two high-resolution density maps, namely that of β-galactosidase at 3.2 Å and TRPV1 at 3.4 Å, we showcase the quality of ReMDFF-generated models, comparing them against ones submitted by independent research groups for the 2015-2016 Cryo-EM Model Challenge. This comparison offers a clear evaluation of ReMDFF's strengths and shortcomings, and those of data-guided real-space refinements in general. ReMDFF results scored highly on the various metric for judging the quality-of-fit and quality-of-model. However, some systematic discrepancies are also noted employing a Molprobity analysis, that are reproducible across multiple competition entries. A space of key refinement parameters is explored within ReMDFF to observe their impact within the final model. Choice of force field parameters and initial model seem to have the most significant impact on ReMDFF model-quality. To this end, very recently developed CHARMM36m force field parameters provide now more refined ReMDFF models than the ones originally submitted to the Cryo-EM challenge. Finally, a set of good-practices is prescribed for the community to benefit from the MDFF developments.

Full Text

Duke Authors

Cited Authors

  • Wang, Y; Shekhar, M; Thifault, D; Williams, CJ; McGreevy, R; Richardson, J; Singharoy, A; Tajkhorshid, E

Published Date

  • November 2018

Published In

Volume / Issue

  • 204 / 2

Start / End Page

  • 319 - 328

PubMed ID

  • 30092279

Pubmed Central ID

  • PMC6394829

Electronic International Standard Serial Number (EISSN)

  • 1095-8657

Digital Object Identifier (DOI)

  • 10.1016/j.jsb.2018.08.003


  • eng

Conference Location

  • United States