Homology Models and Molecular Dynamics Simulations of Main Proteinase from Coronavirus Associated with Severe Acute...

In this study, two structural models (denoted as M^proST and M^proSH) of the main proteinase (M^pro) from the novel coronavirus associated with severe acute respiratory syndrome (SARS-CoV) were constructed based on the crystallographic structures of M^pro from transmissible gastroenteritis coronavirus (TGEV) (M^proT) and human coronavirus HcoV-229E (M^proH), respectively. Various 200 ps molecular dynamics simulations were subsequently performed to investigate the dynamics behaviors of several structural features. Both M^proST and M^proSH exhibit similar folds as their respective template proteins. These structural models reveal three distinct functional domains as well as an intervening loop connecting domains II and III as found in both template proteins. In addition, domain III of these structures exhibits the least secondary structural conservation. A catalytic cleft containing the substrate binding subsites S1 and the S2 between domains I and II are also observed in these structural models. Although these structures share many common features, the most significant difference occurs at the S2 subsite, where the amino acid residues lining up this subsite are least conserved. It may be a critical challenge for designing anti-SARS drugs by simply screening the known database of proteinase inhibitors.