Exploring allosteric communication in multiple states of the bacterial ribosome using residue network analysis

Abstract

Antibiotic resistance is one of the most important problems of our era and hence the discovery of new effective therapeuticsis urgent. At this point, studying the allosteric communication pathways in the bacterial ribosome and revealing allosteric sites/residuesis critical for designing new inhibitors or repurposing readily approved drugs for this enormous machine. To shed light onto moleculardetails of the allosteric mechanisms, here we construct residue networks of the bacterial ribosomal complex at four different states oftranslation by using an effective description of the intermolecular interactions. Centrality analysis of these networks highlights thefunctional roles of structural components and critical residues on the ribosomal complex. High betweenness scores reveal pathways ofresidues connecting numerous sites on the structure. Interestingly, these pathways assemble highly conserved residues, drug bindingsites, and known allosterically linked regions on the same structure. This study proposes a new residue-level model to test how distantsites on the molecular machine may be linked through hub residues that are critically located on the contact topology to inherentlyform communication pathways. Findings also indicate intersubunit bridges B1b, B3, B5, B7, and B8 as critical targets to design novelantibiotics.