Computational prediction of the effect of mutations in the receptor-binding domain on the interaction between SARS-CoV-2 and human ACE2

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 continues to mutate. Numerous studies have indicated that this viral mutation, particularly in the receptor-binding domain area, may increase the viral affinity for human angiotensin-converting enzyme 2 (hACE2), the receptor for viral entry into host cells, thereby increasing viral virulence and transmission. In this study, we investigated the binding affinity of SARS-CoV-2 variants (Delta plus, Iota, Kappa, Mu, Lambda, and C.1.2) on hACE2 using computational modeling with a protein-protein docking approach. The simulation results indicated that there were differences in the interactions between the RBD and hACE2, including hydrogen bonding, salt bridge interactions, non-bonded interactions, and binding free energy differences among these variants. Molecular dynamics simulations revealed that mutations in the RBD increase the stability of the hACE2-spike protein complex relative to the wild type, following the global stability trend and increasing the binding affinity. The value of binding-free energy calculated using molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) indicated that all mutations in the spike protein increased the contagiousness of SARS-CoV-2 variants. The findings of this study provide a foundation for developing effective interventions against these variants.

Genomic and structural mechanistic insight to reveal the differential infectivity of omicron and other variants of concern

“…The predicted docking score from HDOCK for alpha, beta, gamma, delta, omicron and wild type with hACE2 was −307.44, −343.55, −341.54, −343.88, −344.76 and −345.14 kcal/mol respectively. Previous studies have also reported that WT, delta and omicron variants have better docking scores as compared to other variants [ 62 , 63 ]. In a wide-scale analysis of the effects of mutations on RBD–hACE2 affinity, it was reported that approximately 84.3% of mutations did not alter binding affinity, whereas only 3.8% of mutations decreased the binding strength [ 64 ].…”

Prediction of infectivity of SARS-CoV2: Mathematical model with analysis of docking simulation for spike proteins and angiotensin-converting enzyme 2

“…In previous research, only the RBD domain of the spike protein was used in the analysis of binding affinity with ACE2: no MD analysis of the structure optimization ( Celik et al, 2022 ; Gan et al, 2021 ; Shah and Woo, 2021 ; Sitthiyotha and Chunsrivirot, 2021 ; Tragni et al, 2022 ) and/or local optimization of only the RBD domain of the spike protein ( Celik et al, 2022 ; Gan et al, 2021 ; Kumar et al, 2022 ; Shah and Woo, 2021 ; Sitthiyotha and Chunsrivirot, 2021 ; Tragni et al, 2022 ; Xue et al, 2021 ). However, we chose the three-dimensional structure of the complete trimeric spike protein (PDB ID: 6ZGG ) in homology modeling in this research.…”

Prediction of infectivity of SARS-CoV2: Mathematical model with analysis of docking simulation for spike proteins and angiotensin-converting enzyme 2

“…In other previous research, only RBD domain of spike protein were used for the analysis of binding affinity with ACE2 as below: no MD analysis for the structure optimization [22][23][24][25][26] and/or local optimization of only RBD domain [22][23][24][25][26][27][28] of spike protein. However, we choose 3-D structure of whole trimer spike protein (PDB ID: 6ZGG) for homology modeling in this research.…”

“…In previous research, only the RBD domain of the spike protein was used in the analysis of binding affinity with ACE2: no MD analysis of the structure optimization [22][23][24][25][26] and/or local optimization of only the RBD domain [22][23][24][25][26][27][28] of the spike protein.…”