Unraveling motion in proteins by combining NMR relaxometry and molecular dynamics simulations: A case study on ubiquitin

Author:

Champion Candide1ORCID,Lehner Marc1ORCID,Smith Albert A.2ORCID,Ferrage Fabien3ORCID,Bolik-Coulon Nicolas456ORCID,Riniker Sereina1ORCID

Affiliation:

1. Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2 1 , 8093 Zürich, Switzerland

2. Institute for Medical Physics and Biophysics, Leipzig University 2 , Härtelstrasse 16-18, 04107 Leipzig, Germany

3. Laboratoire des Biomolécules, LBM, Département de Chimie, École normale supérieure, PSL University, Sorbonne Université, CNRS 3 , 75005 Paris, France

4. Department of Molecular Genetics, University of Toronto 4 , Toronto, Ontario M5S 1A8, Canada

5. Department of Chemistry, University of Toronto 5 , Toronto, Ontario M5S 3H6, Canada

6. Department of Biochemistry, University of Toronto 6 , Toronto, Ontario M5S 3H6, Canada

Abstract

Nuclear magnetic resonance (NMR) relaxation experiments shine light onto the dynamics of molecular systems in the picosecond to millisecond timescales. As these methods cannot provide an atomically resolved view of the motion of atoms, functional groups, or domains giving rise to such signals, relaxation techniques have been combined with molecular dynamics (MD) simulations to obtain mechanistic descriptions and gain insights into the functional role of side chain or domain motion. In this work, we present a comparison of five computational methods that permit the joint analysis of MD simulations and NMR relaxation experiments. We discuss their relative strengths and areas of applicability and demonstrate how they may be utilized to interpret the dynamics in MD simulations with the small protein ubiquitin as a test system. We focus on the aliphatic side chains given the rigidity of the backbone of this protein. We find encouraging agreement between experiment, Markov state models built in the χ1/χ2 rotamer space of isoleucine residues, explicit rotamer jump models, and a decomposition of the motion using ROMANCE. These methods allow us to ascribe the dynamics to specific rotamer jumps. Simulations with eight different combinations of force field and water model highlight how the different metrics may be employed to pinpoint force field deficiencies. Furthermore, the presented comparison offers a perspective on the utility of NMR relaxation to serve as validation data for the prediction of kinetics by state-of-the-art biomolecular force fields.

Funder

European Research Council

Deutsche Forschungsgemeinschaft

Canadian Institutes of Health Research

Publisher

AIP Publishing

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