Unraveling motion in proteins by combining NMR relaxometry and molecular dynamics simulations: A case study on ubiquitin
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. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000666083Publication status
publishedExternal links
Journal / series
The Journal of Chemical PhysicsVolume
Pages / Article No.
Publisher
American Institute of PhysicsSubject
Water model; Molecular dynamics; Computational methods; Nuclear magnetic resonance; ProteinsFunding
899683 - FET Open – Novel ideas for radically new technologies (EC)
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Is new version of: https://doi.org/10.3929/ethz-b-000644844
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