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Key Interacting Residues between RBD of SARS-CoV-2 and ACE2 Receptor: Combination of Molecular Dynamics Simulation and Density Functional Calculation.

ABSTRACT: The spike protein of SARS-CoV-2 binds to the ACE2 receptor via its receptor-binding domain (RBD), with the RBD-ACE2 complex presenting an essential molecular target for vaccine development to stall the virus infection proliferation. The computational analyses at molecular, amino acid (AA), and atomic levels have been performed systematically to identify the key interacting AAs in the formation of the RBD-ACE2 complex for SARS-CoV and SARS-CoV-2 with its Alpha and Beta variants. Our study uses the molecular dynamics (MD) simulations with the molecular mechanics generalized Born surface area (MM-GBSA) method to predict the binding free energy (BFE) and to determine the actual interacting AAs, as well as two ab initio quantum chemical protocols based on the density functional theory (DFT) implementation. Based on MD results, Q⁴⁹³, Y⁵⁰⁵, Q⁴⁹⁸, N⁵⁰¹, T⁵⁰⁰, N⁴⁸⁷, Y⁴⁴⁹, F⁴⁸⁶, K⁴¹⁷, Y⁴⁸⁹, F⁴⁵⁶, Y⁴⁹⁵, and L⁴⁵⁵ have been identified as hotspots in SARS-CoV-2 RBD, while those in ACE2 are K³⁵³, K³¹, D³⁰, D³⁵⁵, H³⁴, D³⁸, Q²⁴, T²⁷, Y⁸³, Y⁴¹, and E³⁵. RBD with Alpha and Beta variants has slightly different interacting AAs due to N501Y mutation. Both the electrostatic and hydrophobic interactions are the main driving force to form the AA-AA binding pairs. We confirm that Q⁴⁹³, Q⁴⁹⁸, N⁵⁰¹, F⁴⁸⁶, K⁴¹⁷, and F⁴⁵⁶ in RBD are the key residues responsible for the tight binding of SARS-CoV-2 with ACE2 compared to SARS-CoV. RBD with the Alpha variant binds with ACE2 stronger than the wild-type RBD or Beta. In the Beta variant, K417N reduces the binding, E484K slightly enhances it, and N501Y significantly increases it as in Alpha. The DFT results reveal that N⁴⁸⁷, Q⁴⁹³, Y⁴⁴⁹, T⁵⁰⁰, G⁴⁹⁶, G⁴⁴⁶, and G⁵⁰² in RBD of SARS2 form pairs via specific hydrogen bonding with Q²⁴, H³⁴, E³⁵, D³⁸, Y⁴¹, Q⁴², and K³⁵³ in ACE2.

SUBMITTER: Jawad B

PROVIDER: S-EPMC8409146 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe outbreak of coronavirus (SARS-CoV-2) disease caused more than 100,000,000 people get infected and over 2,200,000 people being killed worldwide. However, the current developed vaccines or drugs may be not effective in preventing the pandemic of COVID-19 due to the mutations of coronavirus and the severe side effects of the newly developed vaccines. Chinese herbal medicines and their active components play important antiviral activities. Corilagin exhibited antiviral effect on human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Epstein-Barr virus (EBV). However, whether it blocks the interaction between SARS-CoV-2 RBD and hACE2 has not been elucidated.PurposeTo characterize an active compound, corilagin derived from Phyllanthus urinaria as potential SARS-CoV-2 entry inhibitors for its possible preventive application in daily anti-virus hygienic products.MethodsComputational docking coupled with bio-layer interferometry, BLI were adopted to screen more than 1800 natural compounds for the identification of SARS-CoV-2 spike-RBD inhibitors. Corilagin was confirmed to have a strong binding affinity with SARS-CoV-2-RBD or human ACE2 (hACE2) protein by the BLI, ELISA and immunocytochemistry (ICC) assay. Furthermore, the inhibitory effect of viral infection of corilagin was assessed by in vitro pseudovirus system. Finally, the toxicity of corilagin was examined by using MTT assay and maximal tolerated dose (MTD) studies in C57BL/6 mice.ResultsCorilagin preferentially binds to a pocket that contains residues Cys 336 to Phe 374 of spike-RBD with a relatively low binding energy of -9.4 kcal/mol. BLI assay further confirmed that corilagin exhibits a relatively strong binding affinity to SARS-CoV-2-RBD and hACE2 protein. In addition, corilagin dose-dependently blocks SARS-CoV-2-RBD binding and abolishes the infectious property of RBD-pseudotyped lentivirus in hACE2 overexpressing HEK293 cells, which mimicked the entry of SARS-CoV-2 virus in human host cells. Finally, in vivo studies revealed that up to 300 mg/kg/day of corilagin was safe in C57BL/6 mice. Our findings suggest that corilagin could be a safe and potential antiviral agent against the COVID-19 acting through the blockade of the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors.ConclusionCorilagin could be considered as a safe and environmental friendly anti-SARS-CoV-2 agent for its potential preventive application in daily anti-virus hygienic products.

Project description:Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed over 6 million people and is having a devastating social and economic impact around the world. The rise of new variants of concern (VOCs) represents a difficult challenge due to the loss of vaccine and natural immunity, as well as increased transmissibility. All VOCs contain mutations in the spike glycoprotein, which mediates fusion between the viral and host cell membranes. The spike glycoprotein binds to angiotensin-converting enzyme 2 (ACE2) via its receptor binding domain (RBD) initiating the infection process. Attempting to understand the effect of RBD mutations in VOCs, a lot of attention has been given to the RBD-ACE2 interaction. However, this type of analysis ignores more indirect effects, such as the conformational dynamics of the RBD itself. Observing that some mutations occur in residues that are not in direct contact with ACE2, we hypothesized that they could affect the RBD conformational dynamics. To test this, we performed long atomistic (AA) molecular dynamics (MD) simulations to investigate the structural dynamics of wt RBD, and that of four VOCs (Alpha, Beta, Delta, and Omicron). Our results show that the wt RBD presents two distinct conformations: an "open" conformation where it is free to bind ACE2; and a "closed" conformation, where the RBM ridge blocks the binding surface. The Alpha and Beta variants shift the open/closed equilibrium towards the open conformation by roughly 20%, likely increasing ACE2 binding affinity. Simulations of the Delta and Omicron variants showed extreme results, with the closed conformation being rarely observed. The Delta variant also differed substantially from the other variants, alternating between the open conformation and an alternative "reversed" one, with a significantly changed orientation of the RBM ridge. This alternate conformation could provide a fitness advantage due to increased availability for ACE2 binding, and by aiding antibody escape through epitope occlusion. These results support the hypothesis that VOCs, and particularly the Omicron and Delta variants, impact RBD conformational dynamics in a direction that promotes efficient binding to ACE2 and, in the case of Delta, may assist antibody escape.

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging virus responsible for the ongoing COVID-19 pandemic. SARS-CoV-2 binds to the human cell receptor angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain in the S1 subunit of the spike protein (S1-RBD). The serum levels of autoantibodies against ACE2 are significantly higher in patients with COVID-19 than in controls and are associated with disease severity. However, the mechanisms through which these anti-ACE2 antibodies are induced during SARS-CoV-2 infection are unclear. In this study, we confirmed the increase in antibodies against ACE2 in patients with COVID-19 and found a positive correlation between the amounts of antibodies against ACE2 and S1-RBD. Moreover, antibody binding to ACE2 was significantly decreased in the sera of some COVID-19 patients after preadsorption of the sera with S1-RBD, which indicated that antibodies against S1-RBD can cross-react with ACE2. To confirm this possibility, two monoclonal antibodies (mAbs 127 and 150) which could bind to both S1-RBD and ACE2 were isolated from S1-RBD-immunized mice. Measurement of the binding affinities by Biacore showed these two mAbs bind to ACE2 much weaker than binding to S1-RBD. Epitope mapping using synthetic overlapping peptides and hydrogen deuterium exchange mass spectrometry (HDX-MS) revealed that the amino acid residues P463, F464, E465, R466, D467 and E471 of S1-RBD are critical for the recognition by mAbs 127 and 150. In addition, Western blotting analysis showed that these mAbs could recognize ACE2 only in native but not denatured form, indicating the ACE2 epitopes recognized by these mAbs were conformation-dependent. The protein-protein interaction between ACE2 and the higher affinity mAb 127 was analyzed by HDX-MS and visualized by negative-stain transmission electron microscopy imaging combined with antigen-antibody docking. Together, our results suggest that ACE2-cross-reactive anti-S1-RBD antibodies can be induced during SARS-CoV-2 infection due to potential antigenic cross-reactivity between S1-RBD and its receptor ACE2.

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Key Interacting Residues between RBD of SARS-CoV-2 and ACE2 Receptor: Combination of Molecular Dynamics Simulation and Density Functional Calculation.

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