Narrowing the gap between experimental and computational determination of methyl group dynamics in proteins

Physical Chemistry Chemical Physics : PCCP
Falk HoffmannFrans A A Mulder

Abstract

Nuclear magnetic resonance (NMR) spin relaxation has become the mainstay technique to sample protein dynamics at atomic resolution, expanding its repertoire from backbone 15N to side-chain 2H probes. At the same time, molecular dynamics (MD) simulations have become increasingly powerful to study protein dynamics due to steady improvements of physical models, algorithms, and computational power. Good agreement between generalized Lipari-Szabo order parameters derived from experiment and MD simulation has been observed for the backbone dynamics of a number of proteins. However, the agreement for the more dynamic side-chains, as probed by methyl group relaxation, was much worse. Here, we use T4 lysozyme (T4L), a protein with moderate tumbling anisotropy, to showcase a number of improvements that reduce this gap by a combined evaluation of NMR relaxation experiments and MD simulations. By applying a protein force field with accurate methyl group rotation barriers in combination with a solvation model that yields correct protein rotational diffusion times, we find that properly accounting for anisotropic protein tumbling is an important factor to improve the match between NMR and MD in terms of methyl axis order parameters, spectral...Continue Reading

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Citations

Dec 23, 2019·Structure·Lyudmila Dimitrova-PaternogaJanosch Hennig
May 15, 2021·Current Opinion in Structural Biology·Gogulan KarunanithyD Flemming Hansen
Jul 23, 2021·Journal of Chemical Theory and Computation·Felix KümmererKresten Lindorff-Larsen
Aug 25, 2021·Journal of the American Chemical Society·Xinyao XiangRafael Brüschweiler
Nov 20, 2020·The Journal of Physical Chemistry Letters·Eugene MamontovMatthew B Stone
Nov 12, 2021·Frontiers in Molecular Biosciences·Kai Zumpfe, Albert A Smith
Dec 23, 2021·The Journal of Physical Chemistry. B·Falk HoffmannLars V Schäfer

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Methods Mentioned

BETA
NMR
X-ray

Software Mentioned

LS3
AMBER
CHARMM27
DYNAMICS
ROTDIF
TM
Gromacs
QUADRIC
LS2

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