Contextual Specificity in Peptide-Mediated Protein Interactions

摘要: Most biological processes are regulated through complex networks of transient protein interactions where a globular domain in one recognizes linear peptide from another, creating relatively small contact interface. Although sufficient to ensure binding, these motifs alone usually too short achieve the high specificity observed, and additional contacts often encoded residues surrounding motif (i.e. context). Here, we systematically identified all instances peptide-mediated known three-dimensional structure used them investigate individual contribution context global binding energy. We found that, on average, is responsible for roughly 20% plays crucial role determining interaction specificity, by either improving affinity with native partner or impeding non-native interactions. also studied quantified topological energetic variability interfaces, finding much higher heterogeneity than consensus motifs. Our analysis partially reveals molecular mechanisms dynamic nature interactions, suggests evolutionary mechanism maximise specificity. Finally, investigated viability highlight cases potential cross-reaction that might compensate failure establish backup circuits increase robustness cell networks.