Journal Article

Eigenvector centrality for characterization of protein allosteric pathways

Lisi, George P., Rivalta, Ivan, Hendrickson, Heidi P., Ho, Junming, Batista, Victor S., Morzan, Uriel N., Loria, J. Patrick, Negre, Christian F. A., Pal, Rhitankar

2018

Overview

Determining the principal energy-transfer pathways responsible for allosteric communication in biomolecules remains challenging, partially due to the intrinsic complexity of the systems and the lack of effective characterization methods. In this work, we introduce the eigenvector centrality metric based on mutual information to elucidate allosteric mechanisms that regulate enzymatic activity. Moreover, we propose a strategy to characterize the range of correlations that underlie the allosteric processes. We use the V-type allosteric enzyme imidazole glycerol phosphate synthase (IGPS) to test the proposed methodology. The eigenvector centrality method identifies key amino acid residues of IGPS with high susceptibility to effector binding. The findings are validated by solution NMR measurements yielding important biological insights, including direct experimental evidence for interdomain motion, the central role played by helix hα 1, and the short-range nature of correlations responsible for the allosteric mechanism. Beyond insights on IGPS allosteric pathways and the nature of residues that could be targeted by therapeutic drugs or site-directed mutagenesis, the reported findings demonstrate the eigenvector centrality analysis as a general cost-effective methodology to gain fundamental understanding of allosteric mechanisms at the molecular level.

• Publisher: National Academy of Sciences,National Academy of Sciences, Washington, DC (United States)
• Subject: Allosteric properties / Allosteric Regulation / Allosteric regulation, protein, graphs / Allosteric Site / Amino acids / Aminohydrolases - chemistry / Bacterial Proteins - chemistry / BASIC BIOLOGICAL SCIENCES / Biological Science / Biological Sciences / Biomolecules / Biophysics and Computational Biology / Chemical Sciences / Cost analysis / Eigenvectors / Enzymatic activity / Glycerol / Graph theory / Imidazole / Information theory / Models, Molecular / Models, Theoretical / NMR / Nuclear magnetic resonance / or physical chemistry / PNAS Plus / Protein Binding / Protein Conformation / Proteins / Residues / Site-directed mutagenesis / System effectiveness / Test procedures / Theoretical and