Constant-Ph molecular dynamics simulations of a proton-gated ion channel

Conformational cycling in many macromolecules is modulated by pH. Molecular dynamics (MD) simulations are used routinely to study a variety of structural transitions, for example between functional states of an ion channel. However, in classical MD simulations titratable residues such as aspartic and glutamic acid are assigned fixed protonation states. In reality, such charge states can change dynamically, and may play an important role in functionally relevant mechanisms. Although various MD algorithms have been previously proposed to capture dynamic protonation, their implementations can be computationally intensive or restricted in features, rendering them of limited applicability to large complex systems.