Biomolecular Simulations of Kir Channel Gating and Membrane Phospholipid Interactions

Abstract

Inwardly rectifying potassium (Kir) channels are integral membrane proteins that permit efflux of potassium out of a cell. There are now multiple structures of these channels, existing in a number of different conformational states. Nevertheless, in all of these structures the gate located at the inner transmembrane helix bundle crossing remains closed. In this study we have applied molecular simulations to investigate the dynamics of an extensively validated Kir6.2 channel homology model on the microsecond timescale. Whilst this timescale is insufficient to characterise the full gating process, it provides a means for understanding potential structural changes of the channel in its membrane environment. We have extended this to a multi-scale approach by using coarse-grained (CG) simulations to investigate significant protein-lipid contacts, in particular with phosphotidylinositol containing lipids (eg PIP2), which are known to be involved in channel gating. In addition, we have applied dynamics importance sampling (DIMS) to Kir channel structures and homology models to investigate potential pathways adopted by the channel as it transitions from one state to another. Using these structures, it is possible to explore structural mechanisms for Kir channel gating and hypothesise roles for molecules that modify this process, such as ATP and PIP2.