Journal article
Constant-pH Simulations with the Polarizable Atomic Multipole AMOEBA Force Field
Journal of chemical theory and computation, Vol.20(7), pp.2921-2933
03/20/2024
DOI: 10.1021/acs.jctc.3c01180
PMCID: PMC11008096
PMID: 38507252
Appears in UI Libraries Support Open Access
Abstract
Accurately predicting protein behavior across diverse pH environments remains a significant challenge in biomolecular simulations. Existing constant-pH molecular dynamics (CpHMD) algorithms are limited to fixed-charge force fields, hindering their application to biomolecular systems described by permanent atomic multipoles or induced dipoles. This work overcomes these limitations by introducing the first polarizable CpHMD algorithm in the context of the Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) force field. Additionally, our implementation in the open-source Force Field X (FFX) software has the unique ability to handle titration state changes for crystalline systems including flexible support for all 230 space groups. The evaluation of constant-pH molecular dynamics (CpHMD) with the AMOEBA force field was performed on 11 crystalline peptide systems that span the titrating amino acids (Asp, Glu, His, Lys, and Cys). Titration states were correctly predicted for 15 out of the 16 amino acids present in the 11 systems, including for the coordination of Zn
by cysteines. The lone exception was for a HIS-ALA peptide where CpHMD predicted both neutral histidine tautomers to be equally populated, whereas the experimental model did not consider multiple conformers and diffraction data are unavailable for rerefinement. This work demonstrates the promise polarizable CpHMD simulations for p
predictions, the study of biochemical mechanisms such as the catalytic triad of proteases, and for improved protein-ligand binding affinity accuracy in the context of pharmaceutical lead optimization.
Details
- Title: Subtitle
- Constant-pH Simulations with the Polarizable Atomic Multipole AMOEBA Force Field
- Creators
- Andrew C Thiel - University of IowaMatthew J Speranza - Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa 52242, United StatesSanika Jadhav - Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, Iowa 52242, United StatesLewis L Stevens - University of IowaDaniel K Unruh - University of IowaPengyu Ren - The University of Texas at AustinJay W Ponder - Washington University in St. LouisJana Shen - University of Maryland, BaltimoreMichael J Schnieders - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of chemical theory and computation, Vol.20(7), pp.2921-2933
- DOI
- 10.1021/acs.jctc.3c01180
- PMID
- 38507252
- PMCID
- PMC11008096
- NLM abbreviation
- J Chem Theory Comput
- eISSN
- 1549-9626
- Publisher
- American Chemical Society
- Grant note
- DOI: 10.13039/100000055, name: National Institute on Deafness and Other Communication Disorders, award: R01DC012049; DOI: 10.13039/100000165, name: Division of Chemistry, award: CHE-1751688; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: R01GM106137, R01GM114237, R35GM148261; DOI: 10.13039/100000001, name: National Science Foundation, award: 000390183
- Language
- English
- Electronic publication date
- 03/20/2024
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Core Research Facilities; Pharmaceutical Sciences and Experimental Therapeutics; Biochemistry and Molecular Biology; Chemistry; Chemical and Biochemical Engineering
- Record Identifier
- 9984573950602771
Metrics
15 Record Views