A1 Journal article (refereed)
Best Practices in Constant pH MD Simulations : Accuracy and Sampling (2022)

Buslaev, P., Aho, N., Jansen, A., Bauer, P., Hess, B., & Groenhof, G. (2022). Best Practices in Constant pH MD Simulations : Accuracy and Sampling. Journal of Chemical Theory and Computation, 18(10), 6134-6147. https://doi.org/10.1021/acs.jctc.2c00517

JYU authors or editors

Publication details

All authors or editors: Buslaev, Pavel; Aho, Noora; Jansen, Anton; Bauer, Paul; Hess, Berk; Groenhof, Gerrit

Journal or series: Journal of Chemical Theory and Computation

ISSN: 1549-9618

eISSN: 1549-9626

Publication year: 2022

Publication date: 15/09/2022

Volume: 18

Issue number: 10

Pages range: 6134-6147

Publisher: American Chemical Society (ACS)

Publication country: United States

Publication language: English

DOI: https://doi.org/10.1021/acs.jctc.2c00517

Publication open access: Openly available

Publication channel open access: Partially open access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/83280

Web address of parallel published publication (pre-print): https://doi.org/10.26434/chemrxiv-2022-c6lg2

Abstract

Various approaches have been proposed to include the effect of pH in molecular dynamics (MD) simulations. Among these, the λ-dynamics approach proposed by Brooks and co-workers [Kong, X.; Brooks III, C. L. J. Chem. Phys.1996, 105, 2414−2423] can be performed with little computational overhead and hfor each typeence be used to routinely perform MD simulations at microsecond time scales, as shown in the accompanying paper [Aho, N. et al. J. Chem. Theory Comput.2022, DOI: 10.1021/acs.jctc.2c00516]. At such time scales, however, the accuracy of the molecular mechanics force field and the parametrization becomes critical. Here, we address these issues and provide the community with guidelines on how to set up and perform long time scale constant pH MD simulations. We found that barriers associated with the torsions of side chains in the CHARMM36m force field are too high for reaching convergence in constant pH MD simulations on microsecond time scales. To avoid the high computational cost of extending the sampling, we propose small modifications to the force field to selectively reduce the torsional barriers. We demonstrate that with such modifications we obtain converged distributions of both protonation and torsional degrees of freedom and hence consistent pKa estimates, while the sampling of the overall configurational space accessible to proteins is unaffected as compared to normal MD simulations. We also show that the results of constant pH MD depend on the accuracy of the correction potentials. While these potentials are typically obtained by fitting a low-order polynomial to calculated free energy profiles, we find that higher order fits are essential to provide accurate and consistent results. By resolving problems in accuracy and sampling, the work described in this and the accompanying paper paves the way to the widespread application of constant pH MD beyond pKa prediction.

Keywords: simulation; molecular dynamics; molecules; peptides; proteins; reaction mechanisms; modelling (representation)

Free keywords: computer simulations; molecular mechanics; monomers; peptides and proteins; reaction mechanisms

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Ministry reporting: Yes

Reporting Year: 2022

JUFO rating: 2