{"doi":"10.1021/acs.jpcb.4c05971","title":"Force Field Limitations of All-Atom Continuous Constant pH Molecular Dynamics","abstract":"All-atom constant pH molecular dynamics simulations offer a powerful tool for understanding pH-mediated and proton-coupled biological processes. As the protonation equilibria of protein side chains are shifted by electrostatic interactions and desolvation energies, p K a values calculated from the constant pH simulations may be sensitive to the underlying protein force field and water model. Here we investigated the force field dependence of the all-atom particle mesh Ewald (PME) continuous constant pH (PME-CpHMD) simulations of a mini-protein BBL. The replica-exchange titration simulations based on the Amber ff19sb and ff14sb force fields with the respective water models showed significantly overestimated p K a downshifts for a buried histidine (His166) and for two glutamic acids (Glu141 and Glu161) that are involved in salt-bridge interactions. These errors (due to undersolvation of neutral histidines and overstabilization of salt bridges) are consistent with the previously reported p K a ’s based on the CHARMM c22/CMAP force field, albeit in larger magnitudes. The p K a calculations also demonstrated that ff19sb with OPC water is significantly more accurate than ff14sb with TIP3P water, and the salt-bridge related p K a downshifts can be partially alleviated by the atom-pair specific Lennard-Jones corrections (NBFIX). Together, these data suggest that the accuracies of the protonation equilibria of proteins from constant pH simulations can significantly benefit from improvements of force fields.","journal":"The Journal of Physical Chemistry B","year":2024,"id":439319,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":312676,"name":"Ruibin Liu","orcid":"0000-0001-8395-9353","position":1,"is_corresponding":false},{"id":236994,"name":"Zhong‐Yin Zhang","orcid":"0000-0002-3234-0769","position":2,"is_corresponding":false},{"id":1250000,"name":"Craig A. Peeples","orcid":"0000-0001-6111-6857","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T02:00:47.992543Z","pmid":"39531617","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}