Understanding BirA allostery from a network perspective using MD simulations.

Abstract

Allostery is how two faraway sites communicate to affect their functionality in a biomacromolecule. It is integral to cellular processes like enzymatic catalysis, signal transduction, metabolism, and transcription regulation. The physical manifestations of subtle perturbations, such as amino acid substitutions, on a faraway location can guide us to rationally design allosteric drugs. To explore the effects of remote mutations on a functional site, we work on an allosteric system namely, Biotin Protein Ligase (BPL) extracted from eukaryotic Escherichia coli. This bifunctional BPL allosterically controls homodimerization to bind DNA and repress transcription initiation, as well as catalyze biotin linkage to biotin-dependent carboxylases. Previous thermodynamic studies on various E.coli BPL variants explored the tunability of allosterically modulated homodimerization by performing amino acid substitutions distant from the dimerization site (ranging from weak dimerizers to superdimerizers). In this work, we characterized distinct responses of energy-based protein network architectures to these mutations using Molecular Dynamics simulations and implementing tools from Network theory. Results indicate that the inflow of energetic information to the dimerization site in a protein is correlated to its homodimerization property. Thus, mutations affect functional activity in operating sites by redirecting information traffic in protein residue networks.