Elucidating Interactions Between SARS-CoV-2 Trimeric Spike Protein and ACE2 Using Homology Modeling and Molecular Dynamics Simulations

Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). As of October 21, 2020, more than 41.4 million confirmed cases and 1.1 million deaths have been reported. Thus, it is immensely important to develop drugs and vaccines to combat COVID-19. The spike protein present on the outer surface of the virion plays a major role in viral infection by binding to receptor proteins present on the outer membrane of host cells, triggering membrane fusion and internalization, which enables release of viral ssRNA into the host cell. Understanding the interactions between the SARS-CoV-2 trimeric spike protein and its host cell receptor protein, angiotensin converting enzyme 2 (ACE2), is important for developing drugs and vaccines to prevent and treat COVID-19. Several crystal structures of partial and mutant SARS-CoV-2 spike proteins have been reported; however, an atomistic structure of the wild-type SARS-CoV-2 trimeric spike protein complexed with ACE2 is not yet available. Therefore, in our study, homology modeling was used to build the trimeric form of the spike protein complexed with human ACE2, followed by all-atom molecular dynamics simulations to elucidate interactions at the interface between the spike protein and ACE2. Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) and in silico alanine scanning were employed to characterize the interacting residues at the interface. Twenty interacting residues in the spike protein were identified that are likely to be responsible for tightly binding to ACE2, of which five residues (Val445, Thr478, Gly485, Phe490, and Ser494) were not reported in the crystal structure of the truncated spike protein receptor binding domain (RBD) complexed with ACE2. These data indicate that the interactions between ACE2 and the tertiary structure of the full-length spike protein trimer are different from those between ACE2 and the truncated monomer of the spike protein RBD. These findings could facilitate the development of drugs and vaccines to prevent SARS-CoV-2 infection and combat COVID-19.

In Silico, In Vitro and In Cellulo Models for Monitoring SARS-CoV-2 Spike/Human ACE2 Complex, Viral Entry and Cell Fusion

“…To monitor the S/ACE2 complex and provide data about the dynamics of the interaction, we used previously published structural data [11] for 400 ns molecular dynamics simulations with the AMBER force field and TIP3P water box. Simulations were run with 0.150 M NaCl in a neutral simulation box subject to periodic boundary conditions, in line with previous molecular dynamics studies on the SARS-COV-2 S1 RDB complexed with ACE2 [16,17,18]. The simulation allowed us to precisely model the structural interfaces within the complex ( Figure 1A) and isolate the receptor binding domain of S (RBD).…”

Understanding the molecular interaction of SARS-CoV-2 spike mutants with ACE2 (angiotensin converting enzyme 2)

“…Shortly after the epidemic in China became a pandemic, many groups began to characterize the structure of the viral proteins and its interaction with the receptor, especially the spike protein, interacting with the human angiotensin-converting enzyme 2, ACE2 (Lan et al, 2020 ; Luan et al, 2020 ; Shang et al, 2020 ; Walls et al, 2020 ; Wrapp et al, 2020 ; Yan et al, 2020 ). In the same time, many computational studies were carried out aiming to investigate the spike-ACE2 interactions (Ali & Vijayan, 2020 ; Al-Karmalawy et al, 2021 ; Amin et al, 2020 ; de Andrade et al, 2020 ; Ghorbani et al, 2020 ; Qiao & Olvera de la Cruz, 2020 ; Sakkiah et al, 2020 ; Spinello et al, 2020 ; Verkhivker, 2020 ; Verkhivker & Di Paola, 2021 ; Wang, Liu et al, 2020 ) and feverish bioinformatics-based drug-repurposing (Barros et al, 2020 ; de Oliveira et al, 2021 ; Ekins et al, 2020 ; Idris et al, 2020 ; Sharma et al, 2020 ) and, albeit limited, experimental SARS-CoV-2 inhibition studies were initiated all over the world following the statement of National Institutes of Health (NIH) in April 2020 that the basic genomic layout and the biology of MERS, SARS and SARS-CoV-2 viruses were very similar (Harrison, 2020 ). Repurposed drugs were divided into two groups as ‘acting on the virus’ and ‘acting on the host’, and it was suggested that 20 drugs in the first group and 10 drugs in the second group could be effective in SARS-CoV-2 infections (Singh et al, 2020 ).…”

Homology modeling and mutation prediction of ACE2 from COVID-19

“…Twenty residues interact with proteins and can bind to ACE2, of which five residues (Val445,Thr478,Gly485,Phe490,and Ser494). The interaction between ACE2 and the tertiary structure of the protein is different from that of ACE2 and the RBD protein monomer (Sakkiah et al, 2021).…”