Modeling the Membrane Role in Ca2+-ATPase Catalytic Cycle

Abstract

A deep understanding of the function of membrane proteins requires that we understand the direct and indirect effects of the lipid environment. Deformations of the bilayer to accommodate the protein induce energy penalties and potentially change the free energy between conformational states and thereby change the distribution of protein conformations. The lipid bilayer thus plays a regulatory role for the function of a membrane protein.Structures of the Ca2+-ATPase from sarcoplasmic reticulum, SERCA, have been determined by X-ray crystallography in several different functional states. These structures have provided a unique opportunity to study how the protein interacts with the membrane throughout the functional cycle by all-atom molecular dynamics (MD) simulations.MD simulations have been performed with four different structures of SERCA representing a Ca2+- and ATP-bound state (Ca2E1-ATP); a state with the luminal Ca2+-exit path open and the protein phosphorylated (E2P); and two dephosphorylated occluded states with bound protons, one with inorganic phosphor still bound (E2-Pi) and one without (E2). Our results show how the POPC-membrane and the protein in different functional states undergo mutual adaption (see figure) and how the hydrophobic mismatch and protein area profile change during the functional cycle.View Large Image | View Hi-Res Image | Download PowerPoint Slide