Molecular dynamic simulation suggests stronger in-silico docking of Omicron spike on ACE2 than Wild but weaker than Delta SARS-CoV-2 variants can be blocked by engineered S1-RBD fraction

Abstract Background: The SARS-CoV-2 claimed millions lives globally. Occurring from Wuhan (Wild-type) in December, 2019, it constantly mutated to Omicron (B.1.1.529) the predecessor to Delta. Objectives: Omicron having ~32 spike-mutations has variable infectivity-multiplicity-immunoinvasive properties. Understanding of its mutational-effect on ACE2-binding/disease-severity and developing preventive/therapeutic strategies are important. Methods: The binding-affinities of Wuhan/Delta/Omicron spikes (PDB/GISAID/SWISS-MODEL) were docked (HADDOCK2.4) with ACE2 and compared by competitive-docking (PRODIGY). The protein structural-stability was verified by kinetic-data/Ramachandran-plot (Zlab/UMassMedBioinfo). After several trials, a 59 amino-acid (453ARG-510VAL) peptide-cut (Expasy-server) of the Wild-spike-RBD with some desired mutants (THR500SER/THR500GLY/THR500ALA/THR500CYS) were blindly/competitively docked (PyMOL-V2.2.2) to block the Omicron-ACE2 binding. We examined Molecular-Dynamic-Simulation ( iMOD-server, with 9000-cycles/300k-heating/1-atm pressure for system-equilibration for 50ns-run ) of ACE2 and two CUTs with different SARS-CoV-2 variants. Result: The binding-affinity of Omicron-ACE2 is slightly higher than the rest two in competitive-docking-setup. During individual (1:1) docking, Omicron showed little higher than Wild-type but much weaker binding-affinity than Delta. Competitive-docking suggests that ten H-bonding (1.3Å-2.4Å) with highly favorable energy-values/Van-der-Walls-force/Haddock-score for more stable-binding of Omicron-RBD with ACE2. Blind-docking of different CUTs (wild/mutants) and Omicron to ACE2 completely rejected the Omicron-RBD from ACE2-target. The best blocking/binding affinity of-16.4 and -13Kcal/mole were observed in case of THR500SER and THR500GLY, respectively with multiple H-bonding 1.9Å-2.2Å. These are supported by the MD-simulation results. Conclusion: So the spike binding affinities were Delta>Omicron>wild in 1:1 docking with ACE2. Considering the Wild-type is non-existing nowadays, Omicron showed less ACE2 binding property. The 59Cut of spike-RBD and its mutants THR500SER/THR500GLY may be further screened as universal blocker of this virus.