Using Computational Approaches to Reveal Mechanisms of Kinesin-5 Binding with Microtubule

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Guo, Wenhan
Sanchez, Jason E.
Li, Lin

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Kinesins are microtubule-based motor proteins that play important roles ranging from intracellular transport to cell division. Human Kinesin-5 (Eg5) is essential for mitotic spindle assembly during cell division. By combining molecular dynamics (MD) simulations (MD simulations were performed on Stampede2 at the Texas Advanced Computing Center ( with other multi-scale computational approaches, we systematically studied the interaction between Eg5 and the microtubule. We find the motor domain of Eg5 shows predominantly positive potential at the binding interface to attract the tubulin heterodimer which has negative potential on the binding interface. Electric field lines and electrostatic binding forces are provided, which demonstrate attractive forces between Eg5 and the tubulin heterodimer. Additionally, the folding and binding energy analysis reveals that the Eg5 motor domain performs its functions best when in a weak acidic environment. Molecular dynamics analyses of hydrogen bonds and salt bridges demonstrate that, on the binding interfaces of Eg5 and the tubulin heterodimer, salt bridges play the most significant role in holding the complex. The salt bridge residues on the binding interface of Eg5 are mostly positive, while salt bridge residues on the binding interface of tubulin heterodimer are mostly negative. In contrast, the interface between α and β-tubulins is dominated by hydrogen bonds rather than salt bridges. Compared to the Eg5/α-tubulin interface, the Eg5/β-tubulin interface has a greater number of salt bridges and higher occupancy for salt bridges. This asymmetric salt bridge distribution may play a significant role in Eg5’s directionality. The residues involved in hydrogen bonds and salt bridges are identified in this work and may help guide Eg5-focused anticancer drug design.



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