Structural and simulation analysis of hotspot residues interactions of SARS-CoV 2 with human ACE2 receptor

Abstract

The novel corona virus disease 2019 (SARS-CoV 2) pandemic outbreak was alarming. The binding of SARS-CoV (CoV) spike protein (S-Protein) Receptor Binding Domain (RBD) to Angiotensin converting enzyme 2 (ACE2) receptor initiates the entry of corona virus into the host cells leading to the infection. However, considering the mutations reported in the SARS-CoV 2 (nCoV), the structural changes and the binding interactions of the S-protein RBD of nCoV were not clear. The present study was designed to elucidate the structural changes, hot spot binding residues and their interactions between the nCoV S-protein RBD and ACE2 receptor through computational approaches. Based on the sequence alignment, a total of 58 residues were found mutated in nCoV S-protein RBD. These mutations led to the structural changes in the nCoV S-protein RBD 3d structure with 4 helices, 10 sheets and intermittent loops. The nCoV RBD was found binding to ACE2 receptor with 11 hydrogen bonds and 1 salt bridge. The major hot spot amino acids involved in the binding identified by interaction analysis after simulations includes Glu 35, Tyr 83, Asp 38, Lys 31, Glu 37, His 34 amino acid residues of ACE2 receptor and Gln 493, Gln 498, Asn 487, Tyr 505 and Lys 417 residues in nCoV S-protein RBD. Based on the hydrogen bonding, RMSD and RMSF, total and potential energies, the nCoV was found binding to ACE2 receptor with higher stability and rigidity. Concluding, the hotspots information will be useful in designing blockers for the nCoV spike protein RBD. [Formula: see text]Communicated by Ramaswamy H. Sarma.

Keywords: ACE2 receptor; Novel Coronavirus; hotspots; molecular dynamic simulations; protein interactions; receptor binding domain; spike protein.

Figure 1.

Multiple sequence alignment (MSA) of Spike protein of SARS-CoV (P59594) and nCov (P0DTC2). The Receptor Binding Domain (RBD) region is highlighted in the box.

Figure 2.

Multiple sequence alignment and superimposition of CoV spike protein RBD (PDB Id: 3SCI: chain E) and nCoV spike protein RBD (PDB Id: 6M0J: chain E). a) MSA of CoV spike protein RBD and nCoV spike protein RBD (blue colored arrows signify sheets, orange color cylinder shapes are helices and black line represents loops). b) 3d structures of CoV spike protein RBD (purple) and nCoV spike protein RBD (blue) and c) Super imposition CoV spike protein RBD (purple) and nCoV spike protein RBD (blue).

Figure 3.

Superimposition of ACE2-CoV S-protein RBD complex (PDB Id: 3SCI) with ACE2-nCoV S-protein RBD complex (PDB Id: 6M0J) and interaction profiles. a) Superimposition of ACE2 (orange) - CoV S-protein RBD (purple) with ACE2 (orange) - nCoV S-protein RBD (purple). b) Interactions between ACE2 receptor and CoV S-protein RBD. c) Binding profiles of ACE2 receptor and nCoV S-protein RBD.

Figure 4.

Molecular dynamic simulation analysis of ACE2-CoV S-protein RBD and ACE2- nCoV S-protein RBD a) Deviations graph of ACE2 receptor and CoV S-protein RBD. b) RMSD graphs of ACE2 receptor and nCoV S-protein RBD. c) RMSF graph of ACE2 receptor and CoV S-protein RBD. d) ACE2 receptor and nCoV S-protein RBD residues fluctuation graph.

Figure 5.

Hydrogen bond and energies reported by the ACE2-CoV S-protein RBD (3SCI) and ACE2-nCoV S-protein RBD (6M0J) after simulations. a) Hydrogen bonds graph maintained by the receptor and protein during simulation run b) ACE2 receptor and S-protein RBD of nCoV complex hydrogen bonds graph after simulations studies. c) Average energy and potential energies graph of ACE2-CoV S-protein RBD complex and d) Average energy and potential energies graph of ACE2-nCoV S-protein RBD complex.

Figure 6.

Interaction profiles of ACE2 and nCoV S-protein RBD after simulations and their hotspots a) Binding profile of ACE2-nCoV S-protein RBD complex after 100 ns simulation run. b) Hotspots of nCoV S-protein RBD. c) Important hotspot residues identified in ACE2 receptor.