Free-Energy Landscape of Kinesin by a Realistic Lattice Model

TL;DR

This study uses a realistic lattice model and advanced computational methods to map the free-energy landscape of kinesin, revealing significant subdomain fluctuations linked to its function, which are not captured by traditional elastic models.

Contribution

It introduces a lattice protein model combined with MSOE Monte Carlo and PCA to analyze kinesin's free-energy landscape, highlighting the importance of chain connectivity in functional fluctuations.

Findings

Identification of two key subdomains with partial folding/unfolding.

Structural fluctuations align with recent experimental data.

Large fluctuations are beyond elastic regime, requiring chain connectivity considerations.

Abstract

Structural fluctuations in the thermal equilibrium of the kinesin motor domain are studied using a lattice protein model with Go interactions. By means of the multi-self-overlap ensemble (MSOE) Monte Carlo method and the principal component analysis (PCA), the free-energy landscape is obtained. It is shown that kinesins have two subdomains that exhibit partial folding/unfolding at functionally important regions: one is located around the nucleotide binding site and the other includes the main microtubule binding site. These subdomains are consistent with structural variability that was reported recently based on experimentally-obtained structures. On the other hand, such large structural fluctuations have not been captured by B-factor or normal mode analyses. Thus, they are beyond the elastic regime, and it is essential to take into account chain connectivity for studying the function of kinesins.