Fig 1.
The root mean squared fluctuation (RMSF) per residue plot of the hACE2 receptor obtained from 50 ns molecular dynamics simulation in water at 37 oC (A). The RMSF per residue measures the average deviation of each protein residue over time from a reference position (i.e. the time-averaged displacement of the protein residues). Thus, RMSF analysis reveals the degree of fluctuation of portions of the protein. Inserted is the three-dimensional (3D) superimposition of the average structure of the SARS-CoV-2 S protein and hACE2 receptor complex generated from the molecular dynamics simulation (magenta) and the crystal structure of the SARS-CoV-2 spike protein and hACE2 complex downloaded from RSCB protein data bank (cyan blue) (B). An average root mean square deviation (RMSD) of 0.622 Å was observed for the complex.
Fig 2.
A 2-dimensional visualization of the ligand-residue interactions of the top poses of six peptide drugs at the interaction surface of the hACE2 receptor.
Fig 3.
A heatmap of the count of the hydrogen bond interactions between the six top ranked peptide drugs and amino acid residues present at the interaction surface of the hACE2 receptor (A). Docked poses of one of the peptide drug hits (BV2) on hACE2 receptor that might interfere with the protein-protein interaction between the SARS-CoV-2 spike protein and its human target (hACE2 receptor) (B).
Fig 4.
Top figure shows the plot of RMSD (root mean square deviation) of the interacting surface of hACE2 receptor, in the presence (blue) and absence (red) of docked Sar9 Met (O2)11-Substance P, against the frames from the simulation.
This prediction suggests that there was no significant change in flexibility or conformation of the interacting surface of hACE2 upon binding of the peptide-drug. Bottom figure shows the plot of the number of hydrogen bonds between Sar9 Met (O2)11-Substance P and the hACE2 receptor across the frames from the simulation. The wide fluctuation of the number of hydrogen bonds between the docked ligand and hACE2 receptor might be due to the high flexibility of the docked ligand (a linear decapeptide).
Fig 5.
A plot of the top 10 poses from the spike protein-hACE2 receptor interaction simulation in the presence of docked BV2 (red) and in the absence of docked BV2 (navy blue) on the x-axis and the binding free energies between the protein-protein interactions on the y-axis.
Fig 6.
Plots from the analysis of the molecular dynamic simulation of the predicted protein-protein interaction between SARS-CoV-2 spike protein-hACE2 receptor complex in the presence and absence of the docked BV2.
At the bottom (A), the plot of RMSF and the sequence number of amino acid residues of the spike protein-hACE2 complex in the presence (red) and absence (navy blue) of the docked BV2 is shown. The interaction surfaces are coloured orange in the model of the spike protein-hACE2 complex. Top left (B), shows the plot of RMSD of the interacting surface for hACE2 receptor, in the presence (red) and absence (navy blue) of BV2 within the complex, as a function of simulation time. Top right (C), shows the plot of RMSD of the interacting surface for SARS-CoV-2 spike protein, in the presence (red) and absence (navy blue) of BV2 within the complex, as a function of simulation time.
Table 1.
The table shows a brief description of the preventive and therapeutic potential of two of the predicted top-ranked drugs against COVID-19.