Coupled Residue-Residue Dynamics in Protein Allosteric Mechanisms

Abstract

Although the relationship between structure and function in biomolecules is well established, it is not always adequate to provide a complete understanding of biomolecular function. The dynamical fluctuations of biomolecules can also play an essential role in function. Detailed understanding of how conformational dynamics orchestrates function in allosteric regulation of recognition and catalysis at atomic resolution remains ambiguous. The overarching goal is to understand how biomolecular dynamics are coupled to function by using atomistic molecular simulations to complement experiments. In this talk, we will discuss computational studies on members of a ubiquitous family of enzymes that catalyze peptidyl-prolyl bonds and regulate many sub-cellular processes. We analyze large amount of time-dependent multi-dimensional data with a coarse-grained approach and map key dynamical features within individual macrostates by defining dynamics in terms of residue-residue contacts. The effects of substrate binding are observed to be largely sensed at a location over 15 A from the active site, implying its importance in allostery. Using NMR experiments, we confirm that a dynamic cluster of residues in this distal region is directly coupled to the active site. Furthermore, the dynamical network of inter-residue contacts is coupled and temporally dispersed. Mapping these dynamical features and the coupling of dynamics to function has crucial ramifications in understanding allosteric regulation in enzymes and proteins in general.