These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
Benchmark_v4.pdf (2.68 MB)
Predicting NMR Relaxation of Proteins from Molecular Dynamics Simulations with Accurate Methyl Rotation Barriers
Preprints are manuscripts made publicly available before they have been submitted for formal peer review and publication. They might contain new research findings or data. Preprints can be a draft or final version of an author's research but must not have been accepted for publication at the time of submission.
revised on 27.01.2020 and posted on 27.01.2020by Falk Hoffmann, Frans Mulder, Lars V. Schäfer
The internal dynamics of proteins occurring on time scales from picoseconds to nanoseconds can be sensitively probed by nuclear magnetic resonance (NMR) spin relaxation experiments, as well as by molecular dynamics (MD) simulations. This complementarity oﬀers unique opportunities, provided that the two methods are compared at a suitable level. Recently, several groups have used MD simulations to compute the spectral density of backbone and side-chain molecular motions, and to predict NMR relaxation rates from these. Unfortunately, in the case of methyl groups in protein side-chains, inaccurate energy barriers to methyl rotation were responsible for a systematic discrepancy in the computed relaxation rates, as demonstrated for the AMBER ﬀ99SB*-ILDN force ﬁeld (and related parameter sets), impairing quantitative agreement between simulations and experiments. However, correspondence could be regained by emending the MD force ﬁeld with accurate coupled cluster quantum chemical calculations. Spurred by this positive result, we tested whether this approach could be generally applicable, in spite of the fact that diﬀerent MD force ﬁelds employ diﬀerent water models. Improved methyl group rotation barriers for the CHARMM36 and AMBER ﬀ15ipq protein force ﬁelds were derived, such that the NMR relaxation data obtained from the MD simulations now also display very good agreement with experiment. Results herein showcase the performance of present-day MD force ﬁelds, and manifest their reﬁned ability to accurately describe internal protein dynamics.