Abstract：
: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 h[Formula: see text], 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.
journal_name
Proc Natl Acad Sci U S Aauthors
Negre CFA,Morzan UN,Hendrickson HP,Pal R,Lisi GP,Loria JP,Rivalta I,Ho J,Batista VSdoi
10.1073/pnas.1810452115subject
Has Abstractpub_date
2018-12-26 00:00:00pages
E12201-E12208issue
52eissn
0027-8424issn
1091-6490pii
1810452115journal_volume
115pub_type
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