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

Keywords:

• Spike coronavirus
• antiviral peptide
• alchemical
• binding constant
• ligand-protein complex

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors are thankful to CNPq (Grants 465259/2014-6, 302554/2017-3 and 310166/2020-9), CAPES (Finance code 01), and FAPESP (Grant 2014/50983-3). The authors also acknowledge the FAPERJ NanoHealth Research Network (E-26/010.000983/2019). The FAPERJ Support Program for Thematic Projects in the State of Rio de Janeiro (210.104/2020) and the National Institute of Science and Technology Complex Fluids (INCT-FCx) for funding. ASP was recently awarded the Scientist of Our State by FAPERJ (201.186/2022). He also thanks the research productivity fellowship granted by the CNPq (310166/2020-9).