Folding Molecular Dynamics Simulations of the Transmembrane Peptides of Influenza A, B M2, and MERS-, SARS-CoV E Viral Proteins

Viroporins are small viral proteins that oligomerize in the membrane of host cells and induce the formation of hydrophilic pores in these membranes, thus altering the physiological properties of the host cells. Due to their significance for viral pathogenicity, they have become targets for pharmaceutical intervention, especially through compounds that block their pore-forming activity. Here we add to the growing literature concerning the structure and function of viroporins by studying and comparing -- through molecular dynamics simulations -- the folding of the transmembrane domain peptides of viroporins derived from four viruses : influenza A, influenza B, and the coronaviruses MERS-Cov-2 and SARS-CoV-2. Through a total of more than 50 {\mu}s of simulation time in explicit solvent (TFE) and with full electrostatics, we characterize the folding behavior, helical stability and helical propensity of these transmembrane peptides in their monomeric state and we identify common motifs that may reflect their quaternary organization and/or biological function. We show that the two influenza-derived peptides are significantly different in peptide sequence and secondary structure from the two coronavirus-derived peptides, and that they are organized in two structurally distinct parts : a significantly more stable N-terminal half, and a fast converting C-terminal half that continuously folds and unfolds between $\alpha$-helical structures and non-canonical structures which are mostly turns. In contrast, the two coronavirus-derived transmembrane peptides are much more stable and fast helix formers when compared with the influenza ones. We discuss possible interpretations of these findings and their putative connection to the structural characteristics of the respective viroporins.