Molecular informatics indicates better binding-energetic of Delta
variant (B.1.617.2) with ACE2 than wild, D614G or N501Y CoV-2 is fully
blocked by 84 amino-acid cut of wild CoV-2 spike.
Abstract
The B.1.617.2 known as Delta-variant harbored diverse Spike-mutations.
It is more transmissible than other (wild/D614G/N501Y) with developed
immune-evasion mechanism. Currently, the binding-affinity of these
variant spikes with human lung-ACE2 was evaluated aiming at some
preventive/therapeutic strategies. Structure of spike-variants were
retrieved from PDB/GISAID and used for homology-modeling (SWISS-MODEL).
Different combination of spike-ACE2 binding 1:1 or competitive
blind-docking was performed using Haddock2.4 web-server. After
screening, two cut-segments (84 amino-acid of wild-spike, 432-516 Cut1
and Cut2, an in-silico desired-mutation T500S in Cut1) were tested
(Swiss-model Expasy-server) as blocker/inhibitor of spike-variants
(PyMOL-V2.2.2). Results explored the molecular-basis and energetic of
Delta binding-affinity to ACE2 is far more than others. The numbers of
H-bonding with their average-length, bonding-energy, Van-Der-Walls
energy, Haddock-score were highly favorable for more stable-binding of
Delta-RBD. The Ramachandran-plot (Zlab/UMassMed Bioinfo) data supports a
post-binding stable structural-complex. The best Haddock scores of
-120.8 +/- 2.6 were observed for Delta with Van-Der-Walls and
electrostatic-energy of -62.9 and -208.7, respectively with highest
binding-affinity (ΔG) of -10.7 kcal/mol. Its THR500 and GLN506 strongly
bind with ACE2 LYS353. The Delta-ACE2 complex showed 5 H-bond
(1.7Å-2.8Å) interactions. The Cut1 and its mutant T500S; Cut2 completely
blocked Delta-spike binding to ACE2 with ΔG -8.4 and -10.6 kcal/mol,
respectively. But during competition between 2 Cuts, Cut1 showed better
results. Bioinformatics/molecular-modeling is an emerging field for
screening of some drug/therapeutic targets from numerous options
minimizing time and expenses. Present data unraveled the molecular-basis
of higher affinity of Delta-spike to ACE2 and its
therapeutic-strategies. Laboratory experimental outcome will help for
further validation.