Unveiling Molecular Mechanisms of Kinesin-5 Function Using Multiscale Computational Techniques

Molecular motor protein Kinesin-5 (Eg5) is a member of kinesin superfamily that is critical for bipolar spindle assembly and spindle maintenance during mitosis. As a result it is a promising chemotherapeutic target for cancer treatment. While a number of small-molecule drugs that interact with Eg5 have been identified, little is known about the molecular mechanisms by which they inhibit Eg5 function. Furthermore, multi-motor systems can exhibit qualitatively diverse behavior for drugs that have similar mode of action, in some cases showing distinct dependence of motor velocity on drug concentration. We have studied molecular mechanisms behind function of Eg5 motor in absence and presence of different small-molecular drugs using computational modeling techniques and analytical calculations. Our simulations have revealed pronounced differences in how each drug affects Eg5 mechanochemical cycle and its processivity, while out analytical calculations established a rigorous connection between simulations and experiments. Besides apparent fundamental value this work has significant implications for clinical applications, where in depth understanding of Eg5-drug interaction is important.