Constant pH molecular dynamics simulations: Current status and recent applications

• Published in: Current opinion in structural biology 2022-12, Vol.77, p.102498-102498, Article 102498
• Main Authors: Martins de Oliveira, Vinicius, Liu, Ruibin, Shen, Jana
• Format: Article
• Language: English
• Subjects: Hydrogen-Ion Concentration; Molecular Conformation; Molecular Dynamics Simulation; Protein electrostatics; Proteins - chemistry; Proton transfer; Protons; Structure-function relationships
• ISSN: 0959-440X; 1879-033X
• DOI: 10.1016/j.sbi.2022.102498

Many important protein functions are carried out through proton-coupled conformational dynamics. Thus, the ability to accurately model protonation states dynamically has wide-ranging implications. Over the past two decades, two main types of constant pH methods (discrete and continuous) have been developed to enable proton-coupled molecular dynamics (MD) simulations. In this short review, we discuss the current status of the development and highlight recent applications that have advanced our understanding of protein structure-function relationships. We conclude the review by outlining the remaining challenges in the method development and projecting important areas for future applications. [Display omitted] •The discrete and continuous constant pH methods allow protonation states to respond to conformational dynamics and pH during molecular dynamics (MD) simulations.•Many application studies have focused on the determination of protonation states of various enzymes and explanation of their pH-dependent activities.•Applications to proton-coupled protein-ligand binding and conformational changes of transmembrane proteins are emerging.•The all-atom constant pH methods are most promising but several challenges remain.