Using a comprehensive approach to investigate the interaction between Kinesin-5/Eg5 and the microtubule

Wenhan Guo; Shengjie Sun; Jason E Sanchez; Alan E Lopez-Hernandez; Tolulope A Ale; Jiawei Chen; Tanjina Afrin; Weihong Qiu; Yixin Xie; Lin Li

doi:10.1016/j.csbj.2022.08.020

Using a comprehensive approach to investigate the interaction between Kinesin-5/Eg5 and the microtubule

Comput Struct Biotechnol J. 2022 Aug 11:20:4305-4314. doi: 10.1016/j.csbj.2022.08.020. eCollection 2022.

Authors

Wenhan Guo¹, Shengjie Sun¹, Jason E Sanchez¹, Alan E Lopez-Hernandez¹, Tolulope A Ale¹, Jiawei Chen², Tanjina Afrin^{2

3}, Weihong Qiu³, Yixin Xie⁴, Lin Li^{1

2}

Affiliations

¹ Computational Science Program, University of Texas at El Paso, El Paso, TX, USA.
² Department of Physics, University of Texas at El Paso, El Paso, TX, USA.
³ Department of Physics, Oregon State University, Corvallis, OR, USA.
⁴ Department of Information Technology, Kennesaw State University, Kennesaw, GA, USA.

Abstract

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 with other multi-scale computational approaches, we systematically studied the interaction between Eg5 and the microtubule. We find the electrostatic feature on the motor domains of Eg5 provides attractive interactions to the microtubule. 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. Such salt bridge residue distribution is consistent with electrostatic potential calculations. 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 be helpful for anticancer drug design.

Keywords: DelPhi; DelPhiForce; DelPhiPKa; Eg5; Electrostatic features; Hydrogen bonds; Kinesin-5; Microtubule; Molecular dynamic simulation; Salt bridges; Tubulin.