Browse
Submit Data
Databases
API
Help

Dataset Information

33 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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 (K_d) 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.

SUBMITTER: Williams AH

PROVIDER: S-EPMC8084269 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

mouse ACE2 receptor bound to SARS-CoV-2 variant Beta Spike

Project description: Not available

| EMPIAR-11181 | biostudies-other

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.

| S-EPMC8455130 | biostudies-literature

Decreased interfacial dynamics caused by the N501Y mutation in the SARS-Cov-2 s1 spike:ACE2 complex

Project description: Not available

| S-EPMC8833064 | 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

Decreased Interfacial Dynamics Caused by the N501Y Mutation in the SARS-CoV-2 S1 Spike:ACE2 Complex.

Project description:Coronavirus Disease of 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in a massive health crisis across the globe, with some genetic variants gaining enhanced infectivity and competitive fitness, and thus significantly aggravating the global health concern. In this regard, the recent SARS-CoV-2 alpha, beta, and gamma variants (B.1.1.7, B.1.351, and P.1 lineages, respectively) are of great significance in that they contain several mutations that increase their transmission rates as evident from clinical reports. By the end of March 2021, these variants were accounting for about two-thirds of SARS-CoV-2 variants circulating worldwide. Specifically, the N501Y mutation in the S1 spike receptor binding domain (S1-RBD) of these variants have been reported to increase its affinity for ACE2, although the basis for this is not entirely clear yet. Here, we dissect the mechanism underlying the increased binding affinity of the N501Y mutant for ACE2 using molecular dynamics (MD) simulations of the available ACE2-S1-RBD complex structure (6M0J) and show a prolonged and stable interfacial interaction of the N501Y mutant S1-RBD with ACE2 compared to the wild type S1-RBD. Additionally, we find that the N501Y mutant S1-RBD displays altered dynamics that likely aids in its enhanced interaction with ACE2. By elucidating a mechanistic basis for the increased affinity of the N501Y mutant S1-RBD for ACE2, we believe that the results presented here will aid in developing therapeutic strategies against SARS-CoV-2 including designing of therapeutic agents targeting the ACE2-S1-RBD interaction.

| S-EPMC9355283 | biostudies-literature

mouse ACE2 receptor bound to SARS-CoV-2 variant Omicron BA.2.12.1 Spike

Project description: Not available

| EMPIAR-11180 | biostudies-other

mouse ACE2 receptor bound to SARS-CoV-2 variant Omicron BA.1 Spike

Project description: Not available

| EMPIAR-11179 | biostudies-other

Spreading of a new SARS-CoV-2 N501Y spike variant in a new lineage.

Project description:ObjectivesSurveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomic epidemiology led us to detect several variants since summer 2020. We report the recent spread of a new SARS-CoV-2 spike 501Y variant.MethodsSARS-CoV-2 sequences obtained from human nasopharyngeal samples by Illumina next-generation sequencing were analysed using Nextclade and an in-house Python script and were compared using BLASTn to the GISAID database. Phylogeny was investigated using the IQ-TREE software.ResultsWe identified that SARS-CoV-2 genomes from four patients diagnosed in our institute harboured a new set of amino acid substitutions including L18F, L452R, N501Y, A653V, H655Y, D796Y, G1219V ± Q677H. These spike N501Y genomes are the first of Nextstrain clade 19B. We obtained partial spike gene sequences of this genotype for an additional 43 patients. All patients infected with this genotype were diagnosed since mid-January 2021. We detected 42 other genomes of this genotype in GISAID, which were obtained from samples collected in December 2020 in four individuals and in 2021 in 38 individuals. The 89 sequences obtained in our institute or other laboratories originated from the Comoros archipelago, western European countries (mostly metropolitan France), Turkey and Nigeria.ConclusionThese findings warrant further studies to investigate the spread, epidemiological and clinical features, and sensitivity to immune responses of this variant.

| S-EPMC8114812 | biostudies-literature

In silico analysis of SARS-CoV-2 spike protein N501Y and N501T mutation effects on human ACE2 binding.

Project description:The SARS-CoV-2 is an RNA-based virus and the most vital step of its survival is the attachment to hACE2 through its spike protein. Although SARS-CoV-2 has the ability to maintain high accurate replication and it can be accepted as a low mutation risked virus, it already showed more than nine thousand mutations in spike protein, of which 44 mutations are located within a 3.2 Å interacting distance from the hACE2 receptor. Mutations on spike protein, N501Y and N501T raised serious concerns for higher transmissibility and resistance towards current vaccines. In the current study, the mutational outcomes of N501Y and N501T on the hACE2-SARS CoV-2 spike protein complexation were analyzed by employing all-atom classic molecular dynamics (MD) simulations. These simulations revealed that both N501Y and N501T mutations increased the binding strength of spike protein to the host hACE2, predicted by binding free energy analysis via MM/GBSA rescoring scheme. This study highlights the importance of energy-based analysis for identifying mutational outcomes and will shed light on handling long-term and effective treatment strategies including repurposing anti-viral drugs, anti-SARS-CoV-2 antibodies, vaccines, and antisense based-therapies.

| S-EPMC9247859 | biostudies-literature

human ACE2 receptor bound to SARS-CoV-2 variant Omicron BA.4/5 Spike

Project description: Not available

| EMPIAR-11176 | biostudies-other