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Journal of chemical theory and computation
Dec 24, 2024;20 (24): 10770-10786.

Extended Sampling of Macromolecular Conformations from Uniformly Distributed Points on Multidimensional Normal Mode Hyperspheres.

Antoniel A S Gomes, Mauricio G S Costa, Maxime Louet, Nicolas Floquet, Paulo M Bisch, David Perahia
Author Information
  1. Antoniel A S Gomes: Laboratório de Física Biológica, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil. ORCID
  2. Mauricio G S Costa: Programa de Computação Científica, Vice-Presidência de Educação Informação e Comunicação, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil. ORCID
  3. Maxime Louet: Institut des Biomolecules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, ENSCM, Montpellier Cedex 05 34095, France.
  4. Nicolas Floquet: Institut des Biomolecules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, ENSCM, Montpellier Cedex 05 34095, France.
  5. Paulo M Bisch: Laboratório de Física Biológica, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
  6. David Perahia: Laboratoire de Biologie et Pharmacologie Appliquée (LBPA), UMR 8113, CNRS, École Normale Supérieure Paris-Saclay, Gif-sur-Yvette 91190, France.
PMID: 39663763 DOI: 10.1021/acs.jctc.4c01054

Abstract

Proteins are dynamic entities that adopt diverse conformations, which play a pivotal role in their function. Understanding these conformations is essential, and protein collective motions, particularly those captured by normal mode (NM) and their linear combinations, provide a robust means for conformational sampling. This work introduces a novel approach to obtaining a uniformly oriented set of a given number of lowest frequency NM combined vectors and generating harmonically equidistant restrained structures along them. They are all thus uniformly located on concentric hyperspheres, systematically covering the defined NM space fully. The generated structures are further relaxed with standard molecular dynamics (MD) simulations to explore the conformational space. The efficiency of the approach we termed "distributed points Molecular Dynamics using Normal Modes" (dpMDNM) was assessed by applying it to hen egg-white lysozyme and human cytochrome P450 3A4 (CYP3A4). To this purpose, we compared our new approach with other methods and analyzed the sampling of existing experimental structures. Our results demonstrate the efficacy of dpMDNM in extensive conformational sampling, particularly as more NMs are considered. Ensembles generated by dpMDNM exhibited a broad coverage of the experimental structures, providing valuable insights into the functional aspects of lysozyme and CYP3A4. Furthermore, dpMDNM also covered lysozyme structures with relatively elevated energies corresponding to transient states not easily obtained by standard MD simulations, in conformity with nuclear magnetic resonance structural indications. This method offers an efficient and rational framework for comprehensive protein conformational sampling, contributing significantly to our understanding of protein dynamics and function.

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MeSH Term

Muramidase
Molecular Dynamics Simulation
Cytochrome P-450 CYP3A
Humans
Protein Conformation
Animals
Macromolecular Substances
Chickens

Chemicals

Muramidase
Cytochrome P-450 CYP3A
hen egg lysozyme
CYP3A4 protein, human
Macromolecular Substances
Journal Article

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