The Common Functional Dynamics of Molecular Motor and Switch Proteins

Abstract

Understanding how protein ligand binding can promote distinct conformational states, with different affinities for binding partners, is key to understanding the structural basis of protein efficacy. Here we study eight molecular motor and G-protein families that undergo GTP or ATP associated conformational changes to regulate important cell processes, including signal transduction and intracellular transport. Employing comparative structure analysis, accelerated molecular dynamics and Brownian dynamics simulations we unveil the pervasive similarity of functionally associated dynamical fluctuations. Different families were observed to have variable inactive but common active nucleotide biding site configurations. Activating conformational changes that reconfigure analogous nucleotide binding site residues were also observed in nucleotide free molecular dynamics simulations. This result suggests that this common flexibility is an intrinsic feature of these families. In addition, conformational changes at the nucleotide binding site in all families were observed to accompany the concerted rearrangements of distinct family specific sub-domains. These sub-domains range from 16-202 residues in length and are joined to common core structural elements at topologically equivalent sites. Moreover, structural changes, correlated with those at the nucleotide binding site, were found to alter the geometry, dynamics and electrostatic field properties of these sites. Furthermore, Brownian dynamics simulations reveal that for kinesin, ras, rab, and rho families these electrostatic differences can modulate the kinetics of protein-protein association events. In summary, our accumulated results indicate that similar activating conformational changes link nucleotide binding to distal topologically equivalent sub-domains that in turn play a role in modulating distinct protein-protein interactions. We speculate that this fundamental mechanism operates in all motor and switch proteins. These results have implications for allosteric drug development and future protein engineering efforts on these systems.Images and animations related to this work can be found at: http://thegrantlab.org/