Steered Molecular Dynamics Simulation of Unfolding of Myosin VI Proximal Tail Domain

Abstract

Myosin VI is the only member of the myosin motor protein family that moves towards the minus end of actin filaments. Upon dimerization, myosin VI is capable of processive movement with large step size. Why myosin VI can take such large step size is controversial as there are only two CaM-binding sites on the short lever arms. Based on experimental evidence, we had proposed a model in which myosin VI dimerization triggers an unfolding of the proximal tail domain, a three-helix bundle; such extension could account for the large step size. Here we test the model through molecular dynamics simulation. Steered molecular dynamics simulations proved the feasibility of the proximal tail domain unfolding; the domain was seen to readily unfold with its three helices intact; the extended conformation was found to be stable over time. The simulations, furthermore, revealed interactions between apo-CaM and the proximal tail domain that were not seen in available crystal structures, which stabilize a kink at the beginning of the proximal tail domain.