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The new SARS-CoV-2 strain shows a stronger binding affinity to ACE2 due to N501Y mutant.

ABSTRACT: SARS-CoV-2 is a global challenge due to its ability to spread much faster than the SARS-CoV, which was attributed to the mutations in the receptor binding domain (RBD). These mutations enhanced the electrostatic interactions. Recently, a new strain is reported in the UK that includes a mutation (N501Y) in the RBD, that is possibly increasing the infection rate. Here, using Molecular Dynamics simulations (MD) and Monte Carlo (MC) sampling, we show that the N501 mutation enhanced the electrostatic interactions due to the formation of a strong hydrogen bond between SARS-CoV-2-T500 and ACE2-D355 near the mutation site. In addition, we observed that the electrostatic interactions between the SARS-CoV-2 and ACE2 in the wild type and the mutant are dominated by salt-bridges formed between SARS-CoV-2-K417 and ACE2-D30, SARS-CoV-2-K458, ACE2-E23, and SARS-CoV-2-R403 and ACE2-E37. These interactions contributed more than 40% of the total binding energies.

SUBMITTER: Ali F

PROVIDER: S-EPMC7923861 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Sequence analysis of Indian SARS-CoV-2 isolates shows a stronger interaction of mutant receptor-binding domain with ACE2.

Project description:ObjectiveSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected the whole world, including Odisha, a state in eastern India. Many people have migrated to the state from different countries as well as other states during this SARS-CoV-2 pandemic. The aim of this study was to analyse the receptor-binding domain (RBD) sequence of the spike protein from isolates collected from throat swab samples of COVID-19-positive patients and further to assess the RBD affinity for angiotensin-converting enzyme 2 (ACE2) of different species, including humans.MethodsWhole-genome sequencing for 35 clinical SARS-CoV-2 isolates from COVID-19-positive patients was performed by ARTIC amplicon-based sequencing. Sequence analysis and phylogenetic analysis were performed for the spike region and the RBD region of all isolates. The interaction between the RBD and ACE2 of five different species was also analysed.ResultsThe spike region of 32 isolates showed one or multiple alterations in nucleotide bases in comparison with the Wuhan reference strain. One of the identified mutations, at position 1204 (Ref A, RMRC 22 C), in the RBD coding region of the spike protein showed stronger binding affinity for human ACE2. Furthermore, RBDs of all the Indian isolates showed binding affinity for ACE2 of different species.ConclusionAs mutant RBD showed stronger interaction with human ACE2, it could potentially result in higher infectivity. The binding affinity of the RBDs for ACE2 of all five species studied suggests that the virus can infect a wide variety of animals, which could also act as natural reservoir for SARS-CoV-2.

| S-EPMC7833473 | biostudies-literature

E484K and N501Y SARS-CoV 2 spike mutants Increase ACE2 recognition but reduce affinity for neutralizing antibody.

Project description:SARS-CoV2 mutants B.1.1.7, B.1.351, and P.1 contain a key mutation N501Y. B.1.135 and P.1 lineages have another mutation, E484K. Here, we decode the effect of these two mutations on the host receptor, ACE2, and neutralizing antibody (B38) recognition. The N501Y RBD mutant binds to ACE2 with higher affinity due to improved π-π stacking and π-cation interactions. The higher binding affinity of the E484K mutant is caused due to the formation of additional hydrogen bond and salt-bridge interactions with ACE2. Both the mutants bind to the B38 antibody with reduced affinity due to the loss of several hydrogen-bonding interactions. The insights obtained from the study are crucial to interpret the increased transmissibility and reduced neutralization efficacy of rapidly emerging SARS-CoV2 VOCs.

| S-EPMC8641390 | biostudies-literature

SARS-CoV-2 spike binding to ACE2 is stronger and longer ranged due to glycan interaction.

Project description:Highly detailed steered molecular dynamics simulations are performed on differently glycosylated receptor binding domains of the severe acute respiratory syndrome coronavirus-2 spike protein. The binding strength and the binding range increase with glycosylation. The interaction energy rises very quickly when pulling the proteins apart and only slowly drops at larger distances. We see a catch-slip-type behavior whereby interactions during pulling break and are taken over by new interactions forming. The dominant interaction mode is hydrogen bonds, but Lennard-Jones and electrostatic interactions are relevant as well.

| S-EPMC8648368 | biostudies-literature

An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants.

Project description:The SARS-CoV-2 variants replacing the first wave strain pose an increased threat by their potential ability to escape pre-existing humoral protection. An angiotensin converting enzyme 2 (ACE2) decoy that competes with endogenous ACE2 for binding of the SARS-CoV-2 spike receptor binding domain (S RBD) and inhibits infection may offer a therapeutic option with sustained efficacy against variants. Here, we used Molecular Dynamics (MD) simulation to predict ACE2 sequence substitutions that might increase its affinity for S RBD and screened candidate ACE2 decoys in vitro. The lead ACE2(T27Y/H34A)-IgG1FC fusion protein with enhanced S RBD affinity shows greater live SARS-CoV-2 virus neutralization capability than wild type ACE2. MD simulation was used to predict the effects of S RBD variant mutations on decoy affinity that was then confirmed by testing of an ACE2 Triple Decoy that included an additional enzyme activity-deactivating H374N substitution against mutated S RBD. The ACE2 Triple Decoy maintains high affinity for mutated S RBD, displays enhanced affinity for S RBD N501Y or L452R, and has the highest affinity for S RBD with both E484K and N501Y mutations, making it a viable therapeutic option for the prevention or treatment of SARS-CoV-2 infection with a high likelihood of efficacy against variants.

| S-EPMC8211782 | biostudies-literature

Entropic Overcompensation of the N501Y Mutation on SARS-CoV-2 S Binding to ACE2.

Project description:Recent experimental work has shown that the N501Y mutation in the SARS-CoV-2 S glycoprotein's receptor binding domain (RBD) increases binding affinity to the angiotensin-converting enzyme 2 (ACE2), primarily by overcompensating for a less favorable enthalpy of binding by greatly reducing the entropic penalty for complex formation, but the basis for this entropic overcompensation is not clear [Prévost et al. J. Biol. Chem.2021, 297, 101151]. We use all-atom molecular dynamics simulations and free-energy calculations to qualitatively assess the impact of the N501Y mutation on the enthalpy and entropy of binding of RBD to ACE2. Our calculations correctly predict that N501Y causes a less favorable enthalpy of binding to ACE2 relative to the original strain. Furthermore, we show that this is overcompensated for by a more entropically favorable increase in large-scale quaternary flexibility and intraprotein root mean square fluctuations of residue positions upon binding in both RBD and ACE2. The enhanced quaternary flexibility stems from N501Y's ability to remodel the inter-residue interactions between the two proteins away from interactions central to the epitope and toward more peripheral interactions. These findings suggest that an important factor in determining protein-protein binding affinity is the degree to which fluctuations are distributed throughout the complex and that residue mutations that may seem to result in weaker interactions than their wild-type counterparts may yet result in increased binding affinity thanks to their ability to suppress unfavorable entropy changes upon binding.

| S-EPMC9843633 | biostudies-literature

Fast Prediction of Binding Affinities of the SARS-CoV-2 Spike Protein Mutant N501Y (UK Variant) with ACE2 and Miniprotein Drug Candidates.

Project description:A recently identified variant of SARS-CoV-2 virus, known as the United Kingdom (UK) variant (lineage B.1.1.7), has an N501Y mutation on its spike protein. SARS-CoV-2 spike protein binds with angiotensin-converting enzyme 2 (ACE2), a key protein for the viral entry into the host cells. Here, we report an efficient computational approach, including the simple energy minimizations and binding free energy calculations, starting from an experimental structure of the binding complex along with experimental calibration of the calculated binding free energies, to rapidly and reliably predict the binding affinities of the N501Y mutant with human ACE2 (hACE2) and recently reported miniprotein and hACE2 decoy (CTC-445.2) drug candidates. It has been demonstrated that the N501Y mutation markedly increases the ACE2-spike protein binding affinity (Kd) from 22 to 0.44 nM, which could partially explain why the UK variant is more infectious. The miniproteins are predicted to have ∼10,000- to 100,000-fold diminished binding affinities with the N501Y mutant, creating a need for design of novel therapeutic candidates to overcome the N501Y mutation-induced drug resistance. The N501Y mutation is also predicted to decrease the binding affinity of a hACE2 decoy (CTC-445.2) binding with the spike protein by ∼200-fold. This convenient computational approach along with experimental calibration may be similarly used in the future to predict the binding affinities of potential new variants of the spike protein.

| S-EPMC8084269 | biostudies-literature

Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera.

Project description:Rapidly spreading variants of SARS-CoV-2 that have arisen in the United Kingdom and South Africa share the spike N501Y substitution, which is of particular concern because it is located in the viral receptor binding site for cell entry and increases binding to the receptor (angiotensin converting enzyme 2). We generated isogenic N501 and Y501 SARS-CoV-2. Sera of 20 participants in a previously reported trial of the mRNA-based COVID-19 vaccine BNT162b2 had equivalent neutralizing titers to the N501 and Y501 viruses.

| S-EPMC7805448 | biostudies-literature

Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera.

Project description:Rapidly spreading variants of SARS-CoV-2 that have arisen in the United Kingdom and South Africa share the spike N501Y substitution, which is of particular concern because it is located in the viral receptor binding site for cell entry and increases binding to the receptor. We generated isogenic N501 and Y501 SARS-CoV-2. Twenty human sera from the mRNA-based vaccine BNT162b2 trial exhibited equivalent neutralizing titers to the N501 and Y501 viruses.

| S-EPMC7814835 | biostudies-literature

SARS-CoV-2 Omicron RBD shows weaker binding affinity than the currently dominant Delta variant to human ACE2.

Project description: Not available

| S-EPMC8727475 | biostudies-literature

N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2.

Project description:SARS-CoV-2 has been spreading around the world for the past year. Recently, several variants such as B.1.1.7 (alpha), B.1.351 (beta), and P.1 (gamma), which share a key mutation N501Y on the receptor-binding domain (RBD), appear to be more infectious to humans. To understand the underlying mechanism, we used a cell surface-binding assay, a kinetics study, a single-molecule technique, and a computational method to investigate the interaction between these RBD (mutations) and ACE2. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger interaction, with a faster association rate and a slower dissociation rate. Atomic force microscopy (AFM)-based single-molecule force microscopy (SMFS) consistently quantified the interaction strength of RBD with the mutation as having increased binding probability and requiring increased unbinding force. Molecular dynamics simulations of RBD-ACE2 complexes indicated that the N501Y mutation introduced additional π-π and π-cation interactions that could explain the changes observed by force microscopy. Taken together, these results suggest that the reinforced RBD-ACE2 interaction that results from the N501Y mutation in the RBD should play an essential role in the higher rate of transmission of SARS-CoV-2 variants, and that future mutations in the RBD of the virus should be under surveillance.

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