Developing a consistent model for simulating mechanical and chemical degrees of freedom of stepping kinesin

Molecular motors transform chemical energy into mechanical work to perform important functions in many biological processes. One of the best studied motor proteins is kinesin-1, which steps hand-over hand along microtubules to transport cargo vesicles along the axon of nerve cells, using energy released by the hydrolysis of one ATP molecule in each step. Recent experimental work has provided much insight into the stepping process, which can be interpreted with abstract models of the underlying mechano-chemical cycle. In addition, atomistic simulations have revealed the protein's conformational changes during the stepping stages in detail. However, a consistent picture of kinesin stepping and force generation is still emerging. In particular, experimental data alone does not seem to be sufficient to distinguish between competing mechano-chemical models. One way to address this issue is through a mesoscopic model that is able to simulate many steps of the walker, including missteps, and that treats physical and chemical degrees of freedom in a thermodynamically consistent way. We have been developing a mesoscopic model for Brownian dynamics simulations of kinesin walking on a microtubule and pulling a cargo. Using a simple implementation of a chemical cycle we are able to capture some important aspects of molecular walkers. However, it is difficult to describe the full range of kinesin processes, including failed steps and detachment, in this way. In this work, we broaden the scope of the model and consider more carefully the role of the ATP molecule and its products in the description of the chemical and mechanical states of the system. Our goal is a thermodynamically consistent implementation of mechano-chemical states and transitions so that we may apply our model to more complex problems involving, for example, interactions with obstacles, other kinesins, or multiple microtubules.