Assessment of an Electrostatic Energy-Based Charge Model for Modeling the Electrostatic Interactions in Water Solvent

Xianwei Wang; Yiying Wang; Man Guo; Xuechao Wang; Yang Li; John Z H Zhang

doi:10.1021/acs.jctc.3c00467

Assessment of an Electrostatic Energy-Based Charge Model for Modeling the Electrostatic Interactions in Water Solvent

J Chem Theory Comput. 2023 Sep 26;19(18):6294-6312. doi: 10.1021/acs.jctc.3c00467. Epub 2023 Sep 1.

Authors

Xianwei Wang¹, Yiying Wang¹, Man Guo¹, Xuechao Wang¹, Yang Li², John Z H Zhang^{3

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Affiliations

¹ College of Science, Zhejiang University of Technology, Hangzhou, Zhejiang 310023, China.
² College of Information Science and Engineering, Shandong Agricultural University, Tai'an, Shandong 271018, China.
³ Shenzhen Institute of Synthetic Biology, Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
⁴ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
⁵ NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China.
⁶ Collaborative Innovation Center of Extreme Optics, Shanxi University, Taiyuan, Shanxi 030006, China.

PMID: 37656610
DOI: 10.1021/acs.jctc.3c00467

Abstract

The protein force field based on the restrained electrostatic potential (RESP) charges has limitations in accurately describing hydrogen bonding interactions in proteins. To address this issue, we propose an alternative approach called the electrostatic energy-based charges (EEC) model, which shows improved performance in describing electrostatic interactions (EIs) of hydrogen bonds in proteins. In this study, we further investigate the performance of the EEC model in modeling EIs in water solvent. Our findings demonstrate that the fixed EEC model can effectively reproduce the quantum mechanics/molecular mechanics (QM/MM)-calculated EIs between a water molecule and various water solvent environments. However, to achieve the same level of computational accuracy, the electrostatic potential (ESP) charge model needs to fluctuate according to the electrostatic environment. Our analysis indicates that the requirement for charge adjustments depends on the specific mathematical and physical representation of EIs as a function of the environment for deriving charges. By comparing with widely used empirical water models calibrated to reproduce experimental properties, we confirm that the performance of the EEC model in reproducing QM/MM EIs is similar to that of general purpose TIP4P-like water models such as TIP4P-Ew and TIP4P/2005. When comparing the computed 10,000 distinct EI values within the range of -40 to 0 kcal/mol with the QM/MM results calculated at the MP2/aug-cc-pVQZ/TIP3P level, we noticed that the mean unsigned error (MUE) for the EEC model is merely 0.487 kcal/mol, which is remarkably similar to the MUE values of the TIP4P-Ew (0.63 kcal/mol) and TIP4P/2005 (0.579 kcal/mol) models. However, both the RESP method and the TIP3P model exhibit a tendency to overestimate the EIs, as evidenced by their higher MUE values of 1.761 and 1.293 kcal/mol, respectively. EEC-based molecular dynamics simulations have demonstrated that, when combined with appropriate van der Waals parameters, the EEC model can closely reproduce oxygen-oxygen radial distribution function and density of water, showing a remarkable similarity to the well-established TIP4P-like empirical water models. Our results demonstrate that the EEC model has the potential to build force fields with comparable accuracy to more sophisticated empirical TIP4P-like water models.