Molecular Modeling of SERCA Dynamics and Interactions

Abstract

On a cellular level, the cardiac cycle is orchestrated by release of calcium into the cytosol during systole (contraction) and subsequent reuptake of calcium into internal stores by an ion-motive ATPase during diastole (relaxation). This pump, the sarco(endo)plasmic reticulum calcium ATPase (SERCA), undergoes large conformational changes between enzymatic substates during calcium transport. Recently, we resolved 4 different structural substates of SERCA using intramolecular fluorescence resonance energy transfer (FRET). To investigate SERCA conformational changes in atomic detail we performed molecular dynamics simulations. This technique can directly probe protein motions by using an empirical potential energy function to numerically solve the equations of the motion of the system. We used X-ray crystal structures as a starting point for simulation of open and closed SERCA headpiece conformations and investigated the structural disorder of various structural substates. Specifically, we tested a hypothesis generated from FRET experiments: Open conformations of SERCA are more dynamic than compact, closed structures.