Understanding Ion Channel Gating Mechanisms by Molecular Dynamics Simulations

Drug discovery of membrane proteins, such as ion channels, presents an unprecedented opportunity through recent breakthroughs in the determination of atomic resolution 3D cryo-electron microscopy structures of these proteins. Structure-based drug discovery utilizing in silico methods enables the study of the dynamic connectivity of stable conformations induced by the drug to achieve its effect. With the ever-expanding computational power, simulations of this type reveal protein dynamics in the nano-, micro-, and even millisecond time scales. In the course of hundreds of nanoseconds to a few microseconds, such simulations can capture ion permeation as a result of the gating of ion channel proteins. We call these MD simulations Gating (GMD) as we can see gating and ion permeation during the simulations. Coupled with these technological breakthroughs, our understanding of key common steps regulating the activation of ion channels has matured, allowing us to understand in depth the mechanisms involved in activating an ion channel to perform its function. The insights we have been able to obtain from these GMD simulations have provided an unprecedented understanding of the biological mechanisms of activation of ion channels by PIP₂ and other gating molecules involved and have prepared the road for structure-based drug discovery for this important class of membrane proteins. In this review, we summarize some of these discoveries using GMD from our group as well as others in the field.