A Comparative Study of the Major Biochemical States of Kinesin-MT Complex using Computational Techniques and All-Atom Structural Models

Abstract

Here we apply computational molecular dynamics simulation techniques to do a comprehensive comparative study of the three major biochemical states of a kinesin - microtubule (MT) complex. These states are namely, the nucleotide-free APO state, the ADP-bound state and the ATP-bound state. We built atomistic structure models for these key MT-binding states with different nucleotide content using available crystal structures, homology modeling and flexible fitting of high-quality cryo-electron-microscopy (EM) maps. We next explore how MT binding modulates active site dynamics of kinesin, predict some of the structural changes and pin-point some of the key residues that control the transition states. We further study the binding free-energy between kinesin head and MT in the three states and also identify a list of interactions (hydrogen bonds and salt bridges) between kinesin and MT and also between kinesin and ligand (ADP). We further perform steered molecular dynamics to mimic the intramolecular strain and identify some residues in force regulation of binding affinity. This study helps us identify promising targets for future mutational and functional studies of the kinesin-MT complex.