Remdesivir MD Simulations Suggest a More Favourable Binding to SARS-CoV-2 RNA Dependent RNA Polymerase Mutant P323L Than Wild-Type

Figures

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  Figure 1. (The structure RdRp (PDB ID: 7BV2) [22]. (A) Viral RNA template entry and the NTP entries are shown with black arrowheads, the route for the release of RNA template and product after replication are shown with a black arrow and two dashed black arrows. The NiRAN, b-hairpin, palm fingers, and interface are part of nsp12, nsp8 is depicted in orange and nsp7 in red. The A97V and P332L mutations are depicted in blue. (B) Chemical structure and 3D conformer of Remdesivir (RDV).

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  Figure 2. The H-bonding network or RDV interacting with RdRp residues in (A) WT, (B) A97V, and (C) P323L structures.

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  Figure 3. RMSD plots of 200-ns molecular dynamic simulations of RdRp in apo and complex with RDV. (A) WT−apo and A97V−apo, (B) WT−apo and P323L, (C) WT−RDV and A97V−RDV complex (D) WT−RDV and P323L−RDV complex.

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  Figure 4. RMSF plot of 200-ns simulations of RdRp in apo and complex with RDV. Apo WT, A97V and P323L RdRp (A) and WT-RDV, A97V-RDV complex and (B) P323L-RDV complex.

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  Figure 5. Principal component analyses (PCA) were plotted against each other; Apo WT, A97V and P323L RdRp and WT-RD, A97V-RDV and P33L-RDV RdRp complex.

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  Figure 6. The covariance matrix constructed from the whole MD trajectory fraction of motion of the first 10 eigenvectors plotted against the corresponding eigenvector. The first 10 eigenmodes were used to calculate the percentage fraction of motion of each eigenvector for RdRp-apo (A) and RdRp-RDV (C), and the fraction of motions by a single eigenvector for RdRp-apo (B) and RdRp-RDV complex (D).

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  Figure 7. Free energy landscape (FEL) is represented as a function of PC1 and PC2. Projections of motions in the phase space at 300 K of RdRp WT−apo, A97V−apo, P323 L−apo, WT−RdV, A97V−RDV, P323L−RDV are shown. The first and second PC modes from the PCA of the backbone carbon atom fluctuations were used.