Abstract
The reliability of molecular mechanics simulations to predict effects of ion binding to proteins depends on their ability to simultaneously describe ion-protein, ion-water, and protein-water interactions. Force fields (FFs) to describe protein-water and ion-water interactions have been constructed carefully and have also been refined routinely to improve accuracy. Descriptions for ion-protein interactions have also been refined, although in an a posteriori manner through the use of "nonbonded-fix (NB-fix)"approaches in which parameters from default Lennard-Jones mixing rules are replaced with those optimized against some reference data. However, even after NB-fix corrections, there remains a significant need for improvement. This is also true for polarizable FFs that include self-consistent inducible moments. Our recent studies on the polarizable AMOEBA FF suggested that the problem associated with modeling ion-protein interactions could be alleviated by recalibrating polarization models of cation-coordinating functional groups so that they respond better to the high electric fields present near ions. Here, we present such a recalibration of carbonyls, carboxylates, and hydroxyls in the AMOEBA protein FF and report that it does improve predictions substantially-mean absolute errors in Na+-protein and K+-protein interaction energies decrease from 8.7 to 5.3 and 9.6 to 6.3 kcal/mol, respectively. Errors are computed with respect to estimates from van der Waals-inclusive density functional theory benchmarked against high-level quantum mechanical calculations and experiments. While recalibration does improve ion-protein interaction energies, they still remain underestimated, suggesting that further improvements can be made in a systematic manner through modifications in classical formalism. Nevertheless, we show that by applying our many-body NB-fix correction to Lennard-Jones components, these errors are further reduced to 2.7 and 2.6 kcal/mol, respectively, for Na+ and K+ ions. Finally, we show that the recalibrated AMOEBA protein FF retains its intrinsic reliability in predicting protein structure and dynamics in the condensed phase.
Original language | English |
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Pages (from-to) | 4713-4726 |
Number of pages | 14 |
Journal | Journal of Chemical Information and Modeling |
Volume | 62 |
Issue number | 19 |
DOIs | |
State | Published - 10 Oct 2022 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2022 American Chemical Society.
Funding
The authors acknowledge the use of computer time from Research Computing at USF and funding from the National Institute of Health (Grant no. R01 GM118697). The authors also thank Guy Dayhoff for help with software installation.
Funders | Funder number |
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National Institutes of Health | |
National Institute of General Medical Sciences | R01GM118697 |
University of San Francisco |