A Landscape-Based View on the Stepping Movement of Myosin VI

Abstract

Myosin VI walks towards the minus end of the actin filament with a large and variable step size of about 25-36 nm, which cannot be fully accounted for with the lever-arm-like conformational changes within the two heads. So far, two competing models have been put forward to explain this large step size. Spudich's model (Spink et al., Nat. Struct. Mol. Biol. 15, 591 (2008)) assumes that two myosin VI monomers associate at distal tail, forming a myosin dimer, which makes two full-length Single Alpha Helix (SAH) domains serve as long legs in the dimer. In contrast, the Houdusse-Sweeney model (Mukherjea et al., Mol. Cell 35, 305 (2009)) assumes that the association occurs in the middle of the SAH domain and that the three-helix bundle unfolds to ensure the large step size. Each of these models has experimental grounds, but their consistency with the large and variable step size has not been examined quantitatively. Using a same computational method as we have used for myosin II (Nie et al., PLoS Comput. Biol. 10, e1003552 (2014)), we have theoretically characterized the free energy landscape experienced by the leading head to compare the two proposed models of myosin VI. Our results showed that the leading head is pulled toward the minus end of the actin filament according to the energy bias in the actin-myosin interactions, leading to the variable step size of movement in both two models. However, the large stepping size is realized only in the Spudich model, because in the Houdusse-Sweeney model, unfolding of the three-helix bundle gives rise to the entropic force to shorten the distance between two heads. The stiffness of the SAH domain is a key factor for giving strong free energy bias toward longer stepping distance.