Collective Dynamics Underlying Allosteric Transitions: A Molecular Dynamics Study

Abstract

In all living cells, proteins are performing a vast amount of functions. These functions are often controlled by a mechanism called allosteric regulation. In allosteric regulation, binding affinities in one site are affected by events in distant binding sites. The present study focuses on the protein dynamics underlying the allosteric regulation for the cooperative oxygen binding in hemoglobin and the interaction between the two catalytic sites of ABCE1. To elucidate the mechanism of hemoglobin's cooperativity on an atomistic level, a novel computational technique was developed to analyse the coupling between tertiary and quaternary motions. From Molecular Dynamics simulations showing spontaneous quaternary transitions, the transition trajectories were separated into two orthogonal sets of motions: one consisting of local intra-chain motions only and one consisting of global inter-chain motions only. Using Functional Mode Analysis, a collective motion coupling the two was found. Hydrogen bonds and steric interactions were found to underlie this collective motion in equal measure. In addition, we were able to affect the T-to-R transition rates by choosing different histidine protonation states, thereby providing a possible atomistic explanation for the Bohr effect. ABCE1 is a non-transporting member of the ATP binding cassettes (ABC) proteins family. ATP hydrolysis in the two nucleotide binding domains (NBDs) is associated with a structural change from a closed to an open conformation. The two NBDs in ABCE1 appear structurally symmetric, but bear a peculiar asymmetry: While the mutation of a catalytic Glutamate in the first NBD decreases the overall activity, the same mutation in the second NBD increases the activity. As a first step to investigate the link between the conformational motion and the allosteric interaction, Molecular Dynamics simulations and Essential Dynamics simulations were applied to obtain a structural model of the so far missing closed conformation. Mutations stabilizing the closed conformation were suggested, putatively allowing to derive a structure with X-ray crystallography, which would be an important step towards characterizing the allosteric mechanism of the functional asymmetry.