Structural communication fingerprinting and dynamic investigation of RBD-hACE2 complex from BA.1 × AY.4 recombinant variant (Deltacron) of SARS-CoV-2 to decipher the structural basis for enhanced transmission

Abstract

The BA.1 × AY.4 recombinant variant (Deltacron) continues to inflict chaos globally due to its rapid transmission and infectivity. To decipher the mechanism of pathogenesis by the BA.1 × AY.4 recombinant variant (Deltacron), a protein coupling, protein structural graphs (PSG), residue communication and all atoms simulation protocols were used. We observed that the bonding network is altered by this variant; engaging new residues that helps to robustly bind. HADDOCK docking score for the wild type has been previously reported to be −111.8 ± 1.5 kcal/mol while the docking score for the Deltacron variant was calculated to be −128.3 ± 2.5 kcal/mol. The protein structural graphs revealed variations in the hub residues, number of nodes, inter and intra residues communities, and path communication perturbation caused by the acquired mutations in the Deltacron-RBD thus alter the binding approach and infectivity. Moreover, the dynamic behaviour reported a highly flexible structure with enhanced residues flexibility particularly by the loops required for interaction with ACE2. It was observed that these mutations have altered the secondary structure of the RBD mostly transited to the loops thus acquired higher flexible dynamics than the native structure during the simulation. The total binding free energy for each of these complexes, that is, WT-RBD and Deltacron-RBD were reported to be −61.38 kcal/mol and −70.47 kcal/mol. Protein’s motion revealed a high trace value in the Deltacron variant that clearly depict more structural flexibility. The broad range of phase space covered by the Deltacron variant along PC1 and PC2 suggests that these mutations are important in contributing conformational heterogeneity or flexibility that consequently help the variant to bind more efficiently than the wild type. The current study provides a basis for structure-based drug designing against SARS-CoV-2.

Communicated by Ramaswamy H. Sarma

Keywords:

• Deltacron
• variant
• binding
• simulation
• MM/GBSA

Acknowledgements

The computations were partially performed at the PengCheng Lab. and the Center for High-Performance Computing, Shanghai Jiao Tong University.

Availability of data and material

All the data are available on RCSB, UniProt and any simulation data would be provided on reasonable demand. The accession numbers to access this data are given in the manuscript.

Additional information

Funding

Dong-Qing Wei is supported by grants from the Key Research Area Grant 2016YFA0501703 of the Ministry of Science and Technology of China, the National Science Foundation of China (Grant Nos. 32070662, 61832019, and 32030063), the Science and Technology Commission of Shanghai Municipality (Grant No. 19430750600), as well as SJTU JiRLMDS Joint Research Fund and Joint Research Funds for Medical and Engineering and Scientific Research at Shanghai Jiao Tong University (YG2021ZD02).