for Investigating Conformational Transitions and Environmental Interactions of Proteins.

Proteins are inherently dynamic molecules, and their conformational transitions among various states are essential for numerous biological processes, which are often modulated by their interactions with surrounding environments. Although molecular dynamics (MD) simulations are widely used to investigate these transitions, all-atom (AA) methods are often limited by short time scales and high computational costs, and coarse-grained (CG) implicit-solvent Go̅-like models are usually incapable of studying the interactions between proteins and their environments. Here, we present an approach called Multiple-basin Go̅-Martini, which combines the recent Go̅-Martini model with an exponential mixing scheme to facilitate the simulation of spontaneous protein conformational transitions in explicit environments. We demonstrate the versatility of our method through five diverse case studies: GlnBP, Arc, Hinge, SemiSWEET, and TRAAK, representing ligand-binding proteins, fold-switching proteins, designed proteins, transporters, and mechanosensitive ion channels, respectively. Multiple-basin Go̅-Martini offers a new computational tool for investigating protein conformational transitions, identifying key intermediate states, and elucidating essential interactions between proteins and their environments, particularly protein-membrane interactions. In addition, this approach can efficiently generate thermodynamically meaningful data sets of protein conformational space, which may enhance deep learning-based models for predicting protein conformation distributions.