NMMD: Efficient Cryo-EM Flexible Fitting Based on Simultaneous Normal Mode and Molecular Dynamics atomic displacements

Rémi Vuillemot; Osamu Miyashita; Florence Tama; Isabelle Rouiller; Slavica Jonic

doi:10.1016/j.jmb.2022.167483

NMMD: Efficient Cryo-EM Flexible Fitting Based on Simultaneous Normal Mode and Molecular Dynamics atomic displacements

J Mol Biol. 2022 Apr 15;434(7):167483. doi: 10.1016/j.jmb.2022.167483. Epub 2022 Feb 9.

Authors

Rémi Vuillemot¹, Osamu Miyashita², Florence Tama³, Isabelle Rouiller⁴, Slavica Jonic⁵

Affiliations

¹ IMPMC - UMR 7590 CNRS, Sorbonne Université, Muséum National d'Histoire Naturelle, Paris, France; Department of Biochemistry & Pharmacology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia. Electronic address: https://twitter.com/@RemiVuillemot.
² RIKEN Center for Computational Science, Japan.
³ Department of Physics, Graduate School of Science and Institute of Transformative Bio-Molecules, Nagoya University, Japan. Electronic address: https://twitter.com/@Florence_Tama.
⁴ Department of Biochemistry & Pharmacology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia. Electronic address: https://twitter.com/@IsabellRouill5.
⁵ IMPMC - UMR 7590 CNRS, Sorbonne Université, Muséum National d'Histoire Naturelle, Paris, France. Electronic address: slavica.jonic@upmc.fr.

PMID: 35150654
DOI: 10.1016/j.jmb.2022.167483

Abstract

Atomic models of cryo electron microscopy (cryo-EM) maps of biomolecular conformations are often obtained by flexible fitting of the maps with available atomic structures of other conformations (e.g., obtained by X-ray crystallography). This article presents a new flexible fitting method, NMMD, which combines normal mode analysis (NMA) and molecular dynamics simulation (MD). Given an atomic structure and a cryo-EM map to fit, NMMD simultaneously estimates global atomic displacements based on NMA and local displacements based on MD. NMMD was implemented by modifying EMfit, a flexible fitting method using MD only, in GENESIS 1.4. As EMfit, NMMD can be run with replica exchange umbrella sampling procedure. The new method was tested using a variety of EM maps (synthetic and experimental, with different noise levels and resolutions). The results of the tests show that adding normal modes to MD-based fitting makes the fitting faster (40% in average) and, in the majority of cases, more accurate.

Keywords: cryo electron microscopy (cryo-EM); flexible fitting; molecular dynamics simulation; molecular modeling; normal mode analysis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cryoelectron Microscopy / methods
Crystallography, X-Ray
Molecular Conformation
Molecular Dynamics Simulation*
Protein Conformation