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. 2021 Jul;39(10):3649-3661.
doi: 10.1080/07391102.2020.1768149. Epub 2020 Jun 1.

Elucidating biophysical basis of binding of inhibitors to SARS-CoV-2 main protease by using molecular dynamics simulations and free energy calculations

Md Fulbabu Sk  1 , Rajarshi Roy  1 , Nisha Amarnath Jonniya  1 , Sayan Poddar  1 , Parimal Kar  1
Affiliations

Elucidating biophysical basis of binding of inhibitors to SARS-CoV-2 main protease by using molecular dynamics simulations and free energy calculations

Md Fulbabu Sk et al. J Biomol Struct Dyn. 2021 Jul.

Abstract

The recent outbreak of novel "coronavirus disease 2019" (COVID-19) has spread rapidly worldwide, causing a global pandemic. In the present work, we have elucidated the mechanism of binding of two inhibitors, namely α-ketoamide and Z31792168, to SARS-CoV-2 main protease (Mpro or 3CLpro) by using all-atom molecular dynamics simulations and free energy calculations. We calculated the total binding free energy (ΔGbind) of both inhibitors and further decomposed ΔGbind into various forces governing the complex formation using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal that α-ketoamide is more potent (ΔGbind= - 9.05 kcal/mol) compared to Z31792168 (ΔGbind= - 3.25 kcal/mol) against COVID-19 3CLpro. The increase in ΔGbind for α-ketoamide relative to Z31792168 arises due to an increase in the favorable electrostatic and van der Waals interactions between the inhibitor and 3CLpro. Further, we have identified important residues controlling the 3CLpro-ligand binding from per-residue based decomposition of the binding free energy. Finally, we have compared ΔGbind of these two inhibitors with the anti-HIV retroviral drugs, such as lopinavir and darunavir. It is observed that α-ketoamide is more potent compared to lopinavir and darunavir. In the case of lopinavir, a decrease in van der Waals interactions is responsible for the lower binding affinity compared to α-ketoamide. On the other hand, in the case of darunavir, a decrease in the favorable intermolecular electrostatic and van der Waals interactions contributes to lower affinity compared to α-ketoamide. Our study might help in designing rational anti-coronaviral drugs targeting the SARS-CoV-2 main protease.Communicated by Ramaswamy H. Sarma.

Keywords: COVID-19; MM-PBSA; Molecular Dynamics; SARS-CoV-2 3CLpro; binding free energy.

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Figures

Figure 1.
Figure 1.
(A) The ribbon representation of SARS-CoV-2 3CLpro. The catalytic dyad residues (H41 and C145) are shown in balls and sticks. The inhibitors, α-ketoamide (B) and Z31792168 (C) are represented as sticks.
Figure 2.
Figure 2.
Time evolution of root-mean-square deviations (RMSD) of (A) backbone atoms of 3CLpro relative to their respective minimized structure and (B) heavy atoms of inhibitor.
Figure 3.
Figure 3.
The root-mean-square fluctuations (RMSFs) of Cα atoms for apo (red), 3CLpro/α-ketoamide (green), and 3CLpro/Z31792168 (blue).
Figure 4.
Figure 4.
Dynamic cross-correlation map (DCCM) for (A) apo, (B) 3CLpro/α-ketoamide, and (C) 3CLpro/Z31792168. The extent of correlated and anti-correlated motions are color-coded. Red color shows more anti-correlated motions, and grey color shows correlated motions.
Figure 5.
Figure 5.
Two-dimensional free energy landscapes (FELs) generated by projecting the principal components, PC1 and PC2 for (A) apo, (B) 3CLpro/α-ketoamide, and (C) 3CLpro/Z31792168. The representative structures are shown on the right panel.
Figure 6.
Figure 6.
The two-dimensional free energy landscapes (FELs) of (A) apo, (B) 3CLpro/α-ketoamide, and (C) 3CLpro/Z31792168. FEL obtained from dPCA and their representative structures are shown on the right-hand panel.
Figure 7.
Figure 7.
Energy components (kcal/mol) for the binding of inhibitors to the 3CLpro. ΔEvdW, van der Waals energy; ΔEelect, electrostatics energy in the gas phase; ΔGpolar, polar solvation energy; ΔGnonpolar, nonpolar solvation energy; TΔSMM, configurational entropy contribution and ΔGbind, total binding energy.
Figure 8.
Figure 8.
Decomposition of ΔGbindsim into contributions from individual residues for (A) 3CLpro/α-ketoamide and (B) 3CLpro/Z31792168.
Figure 9.
Figure 9.
The receptor-ligand interaction profile for (A) α-ketoamide and (B) Z31792168. The plots are generated by using Ligplot+. Hydrogen bonds are shown as green dotted lines. Red semicircles show the residues involved in the hydrophobic contacts, and residues involved in hydrogen bonds are represented in green. The inhibitors are described as balls and sticks.
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