Molecular Simulation Study of Kinesin: Coupling between ATPase Domain Conformational Change and Mechanical Stepping

Abstract

Conventional two-headed kinesin is a motor protein that moves unidirectionally by stepping in hand-over-hand manner (akin to human walking) along microtubule (MT) driven by ATP hydrolysis free energy. In the absence of MT, X-ray crystallography revealed primarily two conformations of the head, ATPase domain; “T” structure preferred with a bound ATP and “D” structure preferred with a bound ADP.However, relations among the ATPase conformations, stepping motion, and type of bound nucleotide are still rather unclear. Here, we investigated the coupling mechanism between the enzyme structure and mechanical stepping. For this purpose, we performed molecular dynamics simulations with coarse-grained structure-based models. In particular, to investigate structural preference between T and D in front and rear heads bound on MT, we applied multiple-basin energy landscape model (Okazaki et al., 2006).Through simulations, we found the followings. (1) Enzyme structure can regulate its affinity to MT by the difference in the contact surface area: “T” structure has higher affinity to MT than “D”, which is consistent with experiments. (2) The internal-strain between two heads can regulate the ATPase structural preference: The rear head with forward-directed neck-linker prefer T structure, while the front head with backward-directed neck-linker prefer D structure.