Comparative analysis of human coronavirus E-peptide-PALS-1 interactions using molecular dynamic simulations

The human coronaviruses (hCoVs) SARS-CoV-1, -2, and MERS-CoV are more virulent as they have previously caused severe outbreaks associated with high mortality and morbidity, whereas HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1 are associated with milder, seasonal infections, and therefore less virulent. The envelope (E) protein is present in all hCoVs and harbors a PDZ-binding motif (PBM) that contributes to viral pathogenesis and disease severity by binding to host cell proteins. Each of the seven E proteins are predicted to have a PBM, but it is not known whether the PBM of the less virulent hCoVs can bind stably to host proteins in the same way that the more virulent hCoVs do. This study aimed to investigate this by performing molecular dynamics (MD) simulations of the different E peptides docked to the PALS1 protein, and to assess the stability of these interactions over time. Analysis of the MD simulations showed that the E peptides of the more virulent hCoVs remained attached to PALS1, whereas the E peptides of the less virulent hCoVs detached from PALS1. This was further corroborated by binding free energy calculations, secondary structure analysis, and peptide-protein interaction analysis. The results collectively demonstrated that the binding and stability of the E-PALS1 complex is influenced by both the residues that make up the PBM as well as the immediately preceding residues. This is the first study to investigate the binding capability of the less virulent hCoV E peptides to a host protein and compare it to that of the more virulent hCoV E peptides and offers insight into the varied virulence between the hCoVs. • More virulent hCoV E PBMs are more flexible than less virulent hCoV E PBMs • MD sims show more virulent hCoV E peptides remain attached to PALS1 PDZ • MD analyses show that E PBM sequence differences can impact PALS1 binding • Residues immediately upstream of the E PBM can also influence PALS1 binding • MD data suggests that the hCoV E protein PBM plays a role in hCoV virulence