Biophysical Features and Local Early Conformational Propensities in Intrinsically Disordered Regions of Rhabdoviral Glycoproteins

Most harmful rhabdoviruses cause disease that is invariably lethal to humans, animals and plants. Throughout viral infection, protein refolding is a complex process critical to both receptor recognition and membrane-interacting fusion domains mediated by transmembrane rhabdoviral glycoprotein (Gp). However, little is known about the early stages of context-sensitive structural transitions of the rhabdoviral Gp. We hypothesized that these involve local interactions between residues situated in intrinsically disordered regions (IDRs) of both the β-sheet rich lateral domain and the fusion domain. This study investigates the host-specific biophysical IDRs-determinants encoded in the primary amino acid sequence of rhabdoviral glycoproteins, which are predicted to modulate early conformational events. This can be related to host-specific biophysical features of the local backbone and secondary structure propensities close to or in IDRs of Gps. While showing striking differences between IDRs of N- and C-termini, our results give direct insights into the biophysical folding signals located in these regions and are in congruence with independent experimental observations. Furthermore, on a quantitative scale, the biophysical features of these residues tend to become those that interact the most in the folded structure and are often residues that display evolutionary covariation, reflecting a general tendency toward conserved host-specificity. In conclusion, the accurate connection of biophysical structural features with both IDRs conformational propensities and context-sensitive folding data suggests their statistically significant role in local transition with lasting effects on subsequent conformational states during virus-host interactions and disease-related pathogenicity outcomes.