Avoiding Regions Symptomatic of Conformational and Functional Flexibility to Identify Antiviral Targets in Current and Future Coronaviruses

Rahaman, Jordon; Siltberg-Liberles, Jessica

Viral proteins often possess multifunctionality, mediated by a conformational change in response to environment-specific factors (Xue et al. 2014) . Although conformational flexibility is important for function, it also offers flexibility in what sequence motifs are on display. If these sequences are rapidly diverging, different sequence motifs will be displayed, reinforcing the notion that flexible regions are potentially important in rewiring protein-protein interactions between virus and host (Gitlin et al. 2014) . Although most CoV proteins have almost no intrinsic disorder, several CoV protein families have homologous sites that display loop in some sequences, helix in others and strands in some (table 3, supplementary fig. S3 , Supplementary Material online). These sites are not necessarily disordered but they may be conformationally flexible in realtime (with secondary structure transitions in the same sequence, making them difficult to predict) or on evolutionary time-scales (so that different secondary structure elements actually are present in different sequences). The C(HS) and C(L) sites make up approximately 50-80% of most multiple sequence alignments. With the common expectation that protein structure is more conserved than sequence these numbers are surprisingly low. Neither PSIPRED nor JPred consistently predicts the same state for 20-50% of all sites in these multiple sequence alignments.