A computational comparison of the atomic models of the actomyosin interface

Abstract

Several atomic models of the actomyosin interface have been proposed based on the docking together of their component structures using electron microscopy and resonance energy-transfer measurements. Although these models are in approximate agreement in the location of the binding interfaces when myosin is tightly bound to actin, their relationships to molecular docking simulations based on computational free-energy calculations are investigated here. Both rigid-docking and flexible-docking conformational search strategies were used to identify free-energy minima at the interfaces between atomic models of myosin and actin. These results suggest that the docking model produced by resonance energy-transfer data is closer to a free-energy minimum at the interface than are the available atomic models based on electron microscopy. The conformational searches were performed using both scallop and chicken skeletal muscle myosins and identified similarly oriented actin-binding interfaces that serve to validate that these models are at the global minimum. These results indicate that the existing docking models are close to but not precisely at the lowest-energy initial contact site for strong binding between myosin and actin that should represent an initial contact between the two proteins; therefore, conformational changes are likely to be important during the transition to a strongly bound complex.