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 editorsBuslaev, Pavel; Aho, Noora; Jansen, Anton; Bauer, Paul; Hess, Berk; Groenhof, Gerrit

Journal or seriesJournal of Chemical Theory and Computation



Publication year2022

Publication date15/09/2022


Issue number10

Pages range6134-6147

PublisherAmerican Chemical Society (ACS)

Publication countryUnited States

Publication languageEnglish


Publication open accessOpenly available

Publication channel open accessPartially 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


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.

Keywordssimulationmolecular dynamicsmoleculespeptidesproteinsreaction mechanismsmodelling (representation)

Free keywordscomputer simulations; molecular mechanics; monomers; peptides and proteins; reaction mechanisms

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Reporting Year2022

JUFO rating2

Last updated on 2024-03-04 at 21:46