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Predicting protein functional motions: an old recipe with a new twist

View ORCID ProfileSergei Grudinin, Elodie Laine, Alexandre Hoffmann
doi: https://doi.org/10.1101/703652
Sergei Grudinin
aUniv. Grenoble Alpes, CNRS, Inria, Grenoble INP, LJK, 38000 Grenoble, France
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  • ORCID record for Sergei Grudinin
  • For correspondence: sergei.grudinin@inria.fr
Elodie Laine
bSorbonne Université, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), 75005 Paris, France
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Alexandre Hoffmann
aUniv. Grenoble Alpes, CNRS, Inria, Grenoble INP, LJK, 38000 Grenoble, France
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Abstract

Large macromolecules, including proteins and their complexes, very often adopt multiple conformations. Some of them can be seen experimentally, for example with X-ray crystallography or cryo-electron microscopy. This structural heterogeneity is not occasional and is frequently linked with specific biological function. Thus, the accurate description of macromolecular conformational transitions is crucial for understanding fundamental mechanisms of life’s machinery. We report on a real-time method to predict such transitions by extrapolating from instantaneous eigen-motions, computed using the normal mode analysis, to a series of twists. We demonstrate the applicability of our approach to the prediction of a wide range of motions, including large collective opening-closing transitions and conformational changes induced by partner binding. We also highlight particularly difficult cases of very small transitions between crystal and solution structures. Our method guaranties preservation of the protein structure during the transition and allows to access conformations that are unreachable with classical normal mode analysis. We provide practical solutions to describe localized motions with a few low-frequency modes and to relax some geometrical constraints along the predicted transitions. This work opens the way to the systematic description of protein motions, whatever their degree of collectivity. Our method is available as a part of the NOn-Linear rigid Block (NOLB) package at https://team.inria.fr/nano-d/software/nolb-normal-modes/.

Significance Statement Proteins perform their biological functions by changing their shapes and interacting with each other. Getting access to these motions is challenging. In this work, we present a method that generates plausible physics-based protein motions and conformations. We model a protein as a network of atoms connected by springs and deform it along the least-energy directions. Our main contribution is to perform the deformations in a nonlinear way, through a series of twists. This allows us to produce a wide range of motions, some of them previously inaccessible, and to preserve the structure of the protein during the motion. We are able to simulate the opening or closing of a protein and the changes it undergoes to adapt to a partner.

Footnotes

  • A.H. developed the diagonalization scheme. S.G proposed the twist method and coded the algorithm. E.L. performed the tests and plotted the figures. S.G. and E.L. wrote the manuscript.

  • The authors declare no conflict of interest.

  • https://team.inria.fr/nano-d/software/nolb-normal-modes/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted July 16, 2019.
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Predicting protein functional motions: an old recipe with a new twist
Sergei Grudinin, Elodie Laine, Alexandre Hoffmann
bioRxiv 703652; doi: https://doi.org/10.1101/703652
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Predicting protein functional motions: an old recipe with a new twist
Sergei Grudinin, Elodie Laine, Alexandre Hoffmann
bioRxiv 703652; doi: https://doi.org/10.1101/703652

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