Absolute binding free energies of mucroporin and its analog mucroporin-M1 with the heptad repeat 1 domain and RNA-dependent RNA polymerase of SARS-CoV-2.

ABSTRACT

The peptide Mucroporin and its analog Mucroporin-M1 were studied using the molecular docking and molecular dynamics simulation of their complexation with two protein targets, the Heptad Repeat 1 (HR1) domain and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. The molecular docking of the peptide-protein complexes was performed using the glowworm swarm optimization algorithm. The lowest energy poses were submitted to molecular dynamics simulation. Then, the binding free energies of Mucroporin and its analog Mucroporin-M1 with these two protein targets were calculated using the Multistate Bennett Acceptance Ratio (MBAR) method. It was verified that the peptides/HR1 domain complex showed stability in the interaction site determined by molecular docking. It was also found that Mucroporin-M1 has a much higher affinity than Mucroporin to the HR1 protein target. The peptides showed similar stability and affinity at the NTP binding site in the RdRp protein. Additional experimental studies are needed to confirm the antiviral activity of Mucroporin-M1 and a possible mechanism of action against SARS-CoV-2. However, here we indicate that Mucroporin-M1 may have potential antiviral activity against the HR1 domain with the possibility for further peptide optimization.Communicated by Ramaswamy H. Sarma.