Insights into the structural and dynamical changes of spike glycoprotein mutations associated with SARS-CoV-2 host receptor binding

Ahamad, Shahzaib; Hema, Kanipakam; Gupta, Dinesh

doi:10.1080/07391102.2020.1811774

Cited by 33 publications

(33 citation statements)

References 43 publications

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“…In this study, we were the first to show that the R408I mutation in SARS-CoV-2 is likely to cause a reduced binding affinity to human ACE2 receptor. Our result has been corroborated in several independent studies later on [32][33][34] . Although the S protein gene seems to be more conserved than the other proteinencoding genes in the SARS-CoV-2 genome, our study provides direct evidence that a mutated version of SARS-CoV-2 S protein with varied transmission rate may have already emerged.…”

supporting

confidence: 89%

“…Since then, the R408I mutant has attracted research attention from a significant number of researchers. Both computational and experimental studies have been performed to further investigate its molecular characteristics and potential immune effects [31][32][33][34][35][36][37][38] . In addition, commercial synthesis of the R408I recombinant RBD protein has been offered by serval companies (Acro Biosystems, Creative Dianostics, SinoBiological, and Creative Biolabs) for immuno-binding and diagnostic testing.…”

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confidence: 99%

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Analysis of the mutation dynamics of SARS-CoV-2 reveals the spread history and emergence of RBD mutant with lower ACE2 binding affinity

Jia

Shen

Nguyen

et al. 2020

Preprint

101

100

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Highlights 30• Based on the currently available genome sequence data, we proved that SARS-COV-2 genome has a much lower 31 mutation rate and genetic diversity than SARS during the 2002-2003 outbreak. 32• The spike (S) protein encoding gene of SARS-COV-2 is found relatively more conserved than other protein-encoding 33 genes, which is a good indication for the ongoing antiviral drug and vaccine development. 34• Minimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage 35 spread history. 36• We confirmed a previously reported rearrangement in the S protein arrangement of SARS-COV-2, and propose that 37 this rearrangement should have occurred between human SARS-CoV and a bat SARS-CoV, at a time point much 38 earlier before SARS-COV-2 transmission to human. 39• We provided first evidence that a mutated SARS-COV-2 with reduced human ACE2 receptor binding affinity have 40 emerged in India based on a sample collected on 27 th January 2020. 41 42 130 protein (Accession ID: YP_009724390.1). 131 132

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supporting

confidence: 89%

mentioning

confidence: 99%

Analysis of the mutation dynamics of SARS-CoV-2 reveals the spread history and emergence of RBD mutant with lower ACE2 binding affinity

Jia

Shen

Nguyen

et al. 2020

Preprint

101

100

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“… Location/Source SARS-CoV-2 Genome Variation Associated Phenotypic Changes Ref. Various Genome Sequences Database (Such As Gisaid Database) Analyzing p.614(Asp to Gly) in S (Missense) Higher fatality rate [ 51 ] p.367(Val to Phe) in RBD of S (Missense) p.436(Trp to Arg) in RBD of S (Missense) p.364(Asp to Tyr) in RBD of S (Missense) Higher infectivity (higher affinity to human ACE2 receptors) [ 52 ] p.614(Asp to Gly) in S (Missense) Higher infectivity [ 52 ] p.475(Ala to Val) in RBD of S (Missense) p.452(Leu to Arg) in RBD of S (Missense) p.483(Val to Ala) in RBD of S (Missense) p.490(Phe to Leu) in RBD of S (Missense) Resistant to multiple neutralizing antibodies [ 52 ] p.408(Arg to Ile) in RBD of S (Missense) p.455(Leu to Tyr) in RBD of S (Missense) p.486(Phe to Leu) in RBD of S (Missense) p.493(Gln to Asn) in RBD of S (Missense) p.498(Gln to Tyr) in RBD of S (Missense) p.501(Asn to Thr) in RBD of S (Missense) p.930(Ala to Val) in heptad repeat 1 (HR1) domain of S (Missense) p.936(Asp to Tyr) in heptad repeat 1 (HR1) domain of S (Missense) Reducing stability of spike proteins [ 53 ] p.3691 in NSP6 p.9659 in ORF-10 Reducing the stability of the proteins structures [ 54 ] 8782C > T in ORF-1ab (Synonymous Mutation) 28144T > C in ORF-8 (Missense) 29095C > T in N (Synonymous Mutation) Potential Effects On Transmission and Severity of COVID-19 [ 23 ] Singapore Elimination Of ORF8 (Deletion Of 382 nt) Attenuated Phenotype [ 43 ] During Passaging Virus in Vero-E6 Cells 15-30 nt Deletion in S1/S2 Junction Region Attenuated Phenotype …”

Section: The Sars-cov-2 Mutations and Its Related Variabilities In CLmentioning

confidence: 99%

“…Through in-silico methods, researchers identified the most damaging mutations in two of the functional domains of the viral S protein, including RBD (p.408 (Arg to Ile), p.455 (Leu to Tyr), p.486 (Phe to Leu), p.493 (Gln to Asn), p.498 (Gln to Tyr), and p.501 (Asn to Thr)) and heptad repeat 1 (HR1) domain (p.930 (Ala to Val), p.936 (Asp to Tyr)) [ 53 ]. Another study investigated the S protein mutations and their biological importance by analyzing 80 SARS-CoV-2 variants and 26 mutant ones.…”

Section: The Sars-cov-2 Mutations and Its Related Variabilities In CLmentioning

confidence: 99%

Mutations in SARS-CoV-2; Consequences in structure, function, and pathogenicity of the virus

Bakhshandeh

Jahanafrooz

Abbasi

et al. 2021

Microbial Pathogenesis

120

104

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The third pandemic of coronavirus infection, called COVID-19 disease, began recently in China. The newly discovered coronavirus, entitled SARS-CoV-2, is the seventh member of the human coronaviruses. The main pathogenesis of SARS-CoV-2 infection is severe pneumonia, RNAaemia, accompanied by glass turbidity, and acute cardiac injury. It possesses a single-stranded positive-sense RNA genome which is 60–140 nm in diameter, and has a size of 26–32 kbp . Viral pathogenesis is accomplished with spike glycoprotein through the employment of a membrane-bound aminopeptidase, called the ACE2, as its primary cell receptor. It has been confirmed that various factors such as different national rules for quarantine and various races or genetic backgrounds might influence the mortality and infection rate of COVID-19 in the geographic areas. In addition to various known and unknown factors and host genetic susceptibility, mutations and genetic variabilities of the virus itself have a critical impact on variable clinical features of COVID-19. Although the SARS-CoV-2 genome is more stable than SARS-CoV or MERS-CoV, it has a relatively high dynamic mutation rate with respect to other RNA viruses. It's noteworthy that, some mutations can be founder mutations and show specific geographic patterns. Undoubtedly, these mutations can drive viral genetic variability, and because of genotype-phenotype correlation, resulting in a virus with more/lower/no decrease in natural pathogenic fitness or on the other scenario, facilitating their rapid antigenic shifting to escape the host immunity and also inventing a drug resistance virus, so converting it to a more infectious or deadly virus. Overall, the detection of all mutations in SARS-CoV-2 and their relations with pathological changes is nearly impossible, mostly due to asymptomatic subjects. In this review paper, the reported mutations of the SARS-CoV-2 and related variations in virus structure and pathogenicity in different geographic areas and genotypes are widely investigated. Many studies need to be repeated in other regions/locations for other people to confirm the findings. Such studies could benefit patient-specific therapy, according to genotyping patterns of SARS-CoV-2 distribution.

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“…Protein structures determined via x-ray crystallography have previously been used to provide insights into viral evolution by comparing angstrom scale distances and conformational similarities. MD simulations have already been employed to map the hydrogen bonding topology of the SARS-CoV-2 RBD/ACE2 interaction The goal was to explore the merits of drug repurposing, to characterize mutations, and to determine the stability of binding interactions between the SARS-CoV-2 RBD and several contemporary antiviral drugs (Ahamad et al 2020;Ali and Vijayan 2020;Al-Khafaji et al 2020;Mittal et al 2020;Muralidharan et al 2020;Wang et al 2020;Yu et al 2020). While conventional MD and aMD simulations can provide unprecedented resolution on protein motion over time, interpretations based upon comparisons of single MD trajectories are statistically problematic and difficult to compare.…”

Section: Materials and Methods Molecular Dynamic Simulation -Some Backgroundmentioning

confidence: 99%

Functional binding dynamics relevant to the evolution of zoonotic spillovers in endemic and emergentBetacoronavirusstrains

Rynkiewicz

Babbitt

Cui

et al. 2020

Preprint

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Comparative functional analysis of the binding interactions between various betacoronavirus strains and their potential human target proteins, such as ACE1, ACE2 and CD26, is critical to our future understanding and combating of COVID-19. Here, employing large replicate sets of GPU accelerated molecular dynamics simulations, we statistically compare atom fluctuations of the known human target proteins in both the presence and absence of different strains of the viral receptor binding domain (RBD) of the S spike glycoprotein. We identify a common interaction site between the N-terminal helices of ACE2 and the viral RBD in all strains (hCoV-OC43, hCoV-HKU1, MERS-CoV, SARS-CoV1, and SARS-CoV-2) and a second more dynamically complex RBD interaction site involving the ACE2 amino acid sites K353, Q325, and a novel motif, AAQPFLL (386-392) in the more recent cross-species spillovers (i.e. absent in hCoV-OC43). We use computational mutagenesis to further confirm the functional relevance of these sites. We propose a “one touch/two touch” model of viral evolution potentially involved in functionally facilitating binding interactions in zoonotic spillovers. We also observe these two touch sites governing RBD binding activity in simulations on hybrid models of the suspected viral progenitor, batCoV-HKU4, interacting with both the human SARS target, ACE2, and the human MERS target, CD26. Lastly, we confirm that the presence of a common hypertension drug (lisinopril) within the target site of SARS-CoV-2 bound models of ACE1 and ACE2 acts to enhance the RBD interactions at the same key sites in our proposed model. In the near future, we recommend that our comparative computational analysis identifying these key viral RBD-ACE2 binding interactions be supplemented with comparative studies of site-directed mutagenesis in order to screen for current and future coronavirus strains at high risk of zoonotic transmission to humans.STATEMENT OF SIGNIFICANCEWe generated structural models of the spike glycoprotein receptor binding domain from recent and past betacoronavirus outbreak strains aligned to the angiotensin 1 converting enzyme 2 protein, the primary target protein of the SARS-CoV-2 virus causing COVID 19. We then statistically compared computer simulated molecular dynamics of viral bound and unbound versions of each model to identify locations where interactions with each viral strain have dampened the atom fluctuations during viral binding. We demonstrate that all known strains of betacoronavirus are strongly interactive with the N-terminal helix region of ACE2. We also identify a more complex viral interaction with three novel sites that associates with more recent and deadly SARS strains, and also a bat progenitor strain HKU4.

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Insights into the structural and dynamical changes of spike glycoprotein mutations associated with SARS-CoV-2 host receptor binding

Cited by 33 publications

References 43 publications

Analysis of the mutation dynamics of SARS-CoV-2 reveals the spread history and emergence of RBD mutant with lower ACE2 binding affinity

Analysis of the mutation dynamics of SARS-CoV-2 reveals the spread history and emergence of RBD mutant with lower ACE2 binding affinity

Mutations in SARS-CoV-2; Consequences in structure, function, and pathogenicity of the virus

Functional binding dynamics relevant to the evolution of zoonotic spillovers in endemic and emergentBetacoronavirusstrains

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