Fast assessment of human receptor-binding capability of 2019 novel coronavirus (2019-nCoV)

AbstractThe outbreaks of 2002/2003 SARS, 2012/2015 MERS and 2019/2020 Wuhan respiratory syndrome clearly indicate that genome evolution of an animal coronavirus (CoV) may enable it to acquire human transmission ability, and thereby to cause serious threats to global public health. It is widely accepted that CoV human transmission is driven by the interactions of its spike protein (S-protein) with human receptor on host cell surface; so, quantitative evaluation of these interactions may be used to assess the human transmission capability of CoVs. However, quantitative methods directly using viral genome data are still lacking. Here, we perform large-scale protein-protein docking to quantify the interactions of 2019-nCoV S-protein receptor-binding domain (S-RBD) with human receptor ACE2, based on experimental SARS-CoV S-RBD-ACE2 complex structure. By sampling a large number of thermodynamically probable binding conformations with Monte Carlo algorithm, this approach successfully identified the experimental complex structure as the lowest-energy receptor-binding conformations, and hence established an experiment-based strength reference for evaluating the receptor-binding affinity of 2019-nCoV via comparison with SARS-CoV. Our results show that this binding affinity is about 73% of that of SARS-CoV, supporting that 2019-nCoV may cause human transmission similar to that of SARS-CoV. Thus, this study presents a method for rapidly assessing the human transmission capability of a newly emerged CoV and its mutant strains, and demonstrates that post-genome analysis of protein-protein interactions may provide early scientific guidance for viral prevention and control.

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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

10.1101/2020.04.09.034942 ◽

2020 ◽

Cited By ~ 30

Author(s):

Yong Jia ◽

Gangxu Shen ◽

Yujuan Zhang ◽

Keng-Shiang Huang ◽

Hsing-Ying Ho ◽

...

Keyword(s):

Binding Affinity ◽

Mutation Rate ◽

Receptor Binding ◽

Vaccine Development ◽

Early Stage ◽

Minimum Evolution ◽

S Protein ◽

Phylogeny Analysis ◽

Protein Encoding ◽

Mutation Dynamics

SummaryMonitoring the mutation dynamics of SARS-CoV-2 is critical for the development of effective approaches to contain the pathogen. By analyzing 106 SARS-CoV-2 and 39 SARS genome sequences, we provided direct genetic evidence that SARS-CoV-2 has a much lower mutation rate than SARS. Minimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history. The discrepant phylogenies for the spike protein and its receptor binding domain proved a previously reported structural rearrangement prior to the emergence of SARS-CoV-2. Despite that we found the spike glycoprotein of SARS-CoV-2 is particularly more conserved, we identified a mutation that leads to weaker receptor binding capability, which concerns a SARS-CoV-2 sample collected on 27th January 2020 from India. This represents the first report of a significant SARS-CoV-2 mutant, and raises the alarm that the ongoing vaccine development may become futile in future epidemic if more mutations were identified.HighlightsBased on the currently available genome sequence data, we proved that SARS-COV-2 genome has a much lower mutation rate and genetic diversity than SARS during the 2002-2003 outbreak.The spike (S) protein encoding gene of SARS-COV-2 is found relatively more conserved than other protein-encoding genes, which is a good indication for the ongoing antiviral drug and vaccine development.Minimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history.We confirmed a previously reported rearrangement in the S protein arrangement of SARS-COV-2, and propose that this rearrangement should have occurred between human SARS-CoV and a bat SARS-CoV, at a time point much earlier before SARS-COV-2 transmission to human.We provided first evidence that a mutated SARS-COV-2 with reduced human ACE2 receptor binding affinity have emerged in India based on a sample collected on 27th January 2020.

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pyDockEneRes: per-residue decomposition of protein–protein docking energy

Bioinformatics ◽

10.1093/bioinformatics/btz884 ◽

2019 ◽

Vol 36 (7) ◽

pp. 2284-2285 ◽

Cited By ~ 1

Author(s):

Miguel Romero-Durana ◽

Brian Jiménez-García ◽

Juan Fernández-Recio

Keyword(s):

Binding Affinity ◽

Protein Interactions ◽

Structural Model ◽

Protein Complexes ◽

Complex Structure ◽

Protein Docking ◽

Supplementary Information ◽

Scoring Functions ◽

Residue Decomposition ◽

Docking Energy

Abstract Motivation Protein–protein interactions are key to understand biological processes at the molecular level. As a complement to experimental characterization of protein interactions, computational docking methods have become useful tools for the structural and energetics modeling of protein–protein complexes. A key aspect of such algorithms is the use of scoring functions to evaluate the generated docking poses and try to identify the best models. When the scoring functions are based on energetic considerations, they can help not only to provide a reliable structural model for the complex, but also to describe energetic aspects of the interaction. This is the case of the scoring function used in pyDock, a combination of electrostatics, desolvation and van der Waals energy terms. Its correlation with experimental binding affinity values of protein–protein complexes was explored in the past, but the per-residue decomposition of the docking energy was never systematically analyzed. Results Here, we present pyDockEneRes (pyDock Energy per-Residue), a web server that provides pyDock docking energy partitioned at the residue level, giving a much more detailed description of the docking energy landscape. Additionally, pyDockEneRes computes the contribution to the docking energy of the side-chain atoms. This fast approach can be applied to characterize a complex structure in order to identify energetically relevant residues (hot-spots) and estimate binding affinity changes upon mutation to alanine. Availability and implementation The server does not require registration by the user and is freely accessible for academics at https://life.bsc.es/pid/pydockeneres. Supplementary information Supplementary data are available at Bioinformatics online.

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501Y.V2 and 501Y.V3 variants of SARS-CoV-2 lose binding to Bamlanivimab in vitro

10.1101/2021.02.16.431305 ◽

2021 ◽

Author(s):

Haolin Liu ◽

Pengcheng Wei ◽

Qianqian Zhang ◽

Zhongzhou Chen ◽

Katja Aviszus ◽

...

Keyword(s):

South Africa ◽

Binding Affinity ◽

Receptor Binding ◽

Binding Domain ◽

Therapeutic Antibody ◽

Spike Protein ◽

Receptor Binding Domain ◽

Human Receptor

AbstractWe generated several versions of the receptor binding domain (RBD) of the Spike protein with mutations existing within newly emerging variants from South Africa and Brazil. We found that the mutant RBD with K417N, E484K, and N501Y exchanges has higher binding affinity to the human receptor compared to the wildtype RBD. This mutated version of RBD also completely abolishes the binding to a therapeutic antibody, Bamlanivimab, in vitro.

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Genetic variations and drug repurposing provides key insights into the disruption of the SARS COV2

10.31219/osf.io/b7y2c ◽

2020 ◽

Cited By ~ 1

Author(s):

Gayatri Panda ◽

Neha Mishra ◽

Arjun Ray

Keyword(s):

Drug Repurposing ◽

Genetic Variations ◽

Protein Docking ◽

Receptor Protein ◽

Energy Estimation ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Drug Molecules ◽

Initial Interaction ◽

Human Receptor

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) is mediated via the initial interaction of the virus’s spike (S-) protein with a human receptor protein called angiotensin-converting enzyme 2 (hACE2). Interference in this association can have immense therapeutic importance. We used an in-silico combinatorial approach involving homology-based protein modeling, protein-protein docking, binding energy estimation and virtual screening techniques to probe for genetic variations and drug molecules for disruption of the hACE2-CoV2 interaction. Our results identified Ser19Pro variation on hACE2 showed similar structural stability to the native protein while having a destabilizing effect in the hACE2(Ser19Pro)-S-protein complex. We also found several FDA-approved drug molecules that can potentially induce competition-mediated destabilization of the hACE2-CoV2 complex. In conclusion, these findings provide critical insights for intervention strategies targeting the pathogenicity of SARS-CoV-2.

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Structural remodeling of SARS-CoV-2 spike protein glycans reveals the regulatory roles in receptor binding affinity

10.1101/2021.08.26.457782 ◽

2021 ◽

Author(s):

Yen-Pang Hsu ◽

Debopreeti Mukherjee ◽

Vladimir Shchurik ◽

Alexey Makarov ◽

Benjamin F. Mann

Keyword(s):

Binding Affinity ◽

Receptor Binding ◽

Binding Domain ◽

Spike Protein ◽

Receptor Binding Domain ◽

S Protein ◽

Receptor Binding Affinity ◽

Protein Receptor ◽

Regulatory Effects

AbstractGlycans of the SARS-CoV-2 spike protein are speculated to play functional roles in the infection processes as they extensively cover the protein surface and are highly conserved across the variants. To date, the spike protein has become the principal target for vaccine and therapeutic development while the exact effects of its glycosylation remain elusive. Experimental reports have described the heterogeneity of the spike protein glycosylation profile. Subsequent molecular simulation studies provided a knowledge basis of the glycan functions. However, there are no studies to date on the role of discrete glycoforms on the spike protein pathobiology. Building an understanding of its role in SARS-CoV-2 is important as we continue to develop effective medicines and vaccines to combat the disease. Herein, we used designed combinations of glycoengineering enzymes to simplify and control the glycosylation profile of the spike protein receptor-binding domain (RBD). Measurements of the receptor binding affinity revealed the regulatory effects of the RBD glycans. Remarkably, opposite effects were observed from differently remodeled glycans, which presents a potential strategy for modulating the spike protein behaviors through glycoengineering. Moreover, we found that the reported anti-SARS-CoV-(2) antibody, S309, neutralizes the impact of different RBD glycoforms on the receptor binding affinity. Overall, this work reports the regulatory roles that glycosylation plays in the interaction between the viral spike protein and host receptor, providing new insights into the nature of SARS-CoV-2. Beyond this study, enzymatic remodeling of glycosylation offers the opportunity to understand the fundamental role of specific glycoforms on glycoconjugates across molecular biology.Covert art LegendsThe glycosylation of the SARS-CoV-2 spike protein receptor-binding domain has regulatory effects on the receptor binding affinity. Sialylation or not determines the “stabilizing” or “destabilizing” effect of the glycans. (Protein structure model is adapted from Protein Data Bank: 6moj. The original model does not contain the glycan structure.)SignificanceGlycans extensively cover the surface of SARS-CoV-2 spike (S) protein but the relationships between the glycan structures and the protein pathological behaviors remain elusive. Herein, we simplified and harmonized the glycan structures in the S protein receptor-binding domain and reported their regulatory roles in human receptor interaction. Opposite regulatory effects were observed and were determined by discrete glycan structures, which can be neutralized by the reported S309 antibody binding to the S protein. This report provides new insight into the mechanism of SARS-CoV-2 S protein infection as well as S309 neutralization.

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Interactions of the Receptor Binding Domain of SARS-CoV-2 Variants with hACE2: Insights from Molecular Docking Analysis and Molecular Dynamic Simulation

Biology ◽

10.3390/biology10090880 ◽

2021 ◽

Vol 10 (9) ◽

pp. 880

Author(s):

Ismail Celik ◽

Rohitash Yadav ◽

Zekeriya Duzgun ◽

Sarah Albogami ◽

Ahmed M. El-Shehawi ◽

...

Keyword(s):

Receptor Binding ◽

Experimental Studies ◽

Point Mutations ◽

Protein Docking ◽

Binding Domain ◽

Host Cells ◽

Dynamics Simulation ◽

Receptor Binding Domain ◽

S Protein ◽

The Impact

Since the beginning of the coronavirus 19 (COVID-19) pandemic in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been evolving through the acquisition of genomic mutations, leading to the emergence of multiple variants of concern (VOCs) and variants of interest (VOIs). Currently, four VOCs (Alpha, Beta, Delta, and Gamma) and seven VOIs (Epsilon, Zeta, Eta, Theta, Iota, Kappa, and Lambda) of SARS-CoV-2 have been identified in worldwide circulation. Here, we investigated the interactions of the receptor-binding domain (RBD) of five SARS-CoV-2 variants with the human angiotensin-converting enzyme 2 (hACE2) receptor in host cells, to determine the extent of molecular divergence and the impact of mutation, using protein-protein docking and dynamics simulation approaches. Along with the wild-type (WT) SARS-CoV-2, this study included the Brazilian (BR/lineage P.1/Gamma), Indian (IN/lineage B.1.617/Delta), South African (SA/lineage B.1.351/Beta), United Kingdom (UK/lineage B.1.1.7/Alpha), and United States (US/lineage B.1.429/Epsilon) variants. The protein-protein docking and dynamics simulation studies revealed that these point mutations considerably affected the structural behavior of the spike (S) protein compared to the WT, which also affected the binding of RBD with hACE2 at the respective sites. Additional experimental studies are required to determine whether these effects have an influence on drug–S protein binding and its potential therapeutic effect.

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Evolution of Human Receptor Binding Affinity of H1N1 Hemagglutinins from 1918 to 2009 Pandemic Influenza A Virus

Journal of Chemical Information and Modeling ◽

10.1021/ci100038g ◽

2010 ◽

Vol 50 (8) ◽

pp. 1410-1417 ◽

Cited By ~ 27

Author(s):

Nadtanet Nunthaboot ◽

Thanyada Rungrotmongkol ◽

Maturos Malaisree ◽

Nopporn Kaiyawet ◽

Panita Decha ◽

...

Keyword(s):

Binding Affinity ◽

Influenza A Virus ◽

Receptor Binding ◽

Pandemic Influenza ◽

Influenza A ◽

Receptor Binding Affinity ◽

Human Receptor

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Catechin and curcumin interact with S protein of SARS-CoV2 and ACE2 of human cell membrane: insights from computational studies

Scientific Reports ◽

10.1038/s41598-021-81462-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Atala B. Jena ◽

Namrata Kanungo ◽

Vinayak Nayak ◽

G. B. N. Chainy ◽

Jagneshwar Dandapat

Keyword(s):

Amino Acid ◽

Binding Affinity ◽

Receptor Binding ◽

Computational Study ◽

Cell Receptor ◽

Binding Domain ◽

Spike Protein ◽

Receptor Binding Domain ◽

Amino Acid Residues ◽

S Protein

AbstractThe recent outbreak of the coronavirus (SARS-CoV2) is an unprecedented threat to human health and society across the globe. In this context, development of suitable interventions is the need of the hour. The viral spike protein (S Protein) and the cognate host cell receptor ACE2 can be considered as effective and appropriate targets for interventions. It is evident from the present computational study, that catechin and curcumin, not only exhibit strong binding affinity to viral S Protein and host receptor ACE2 but also to their complex (receptor-binding domain (RBD) of the spike protein of SARS-CoV2 and ACE2; RBD/ACE2-complex). The binding affinity values of catechin and curcumin for the S protein, ACE2 and RBD/ACE2-complex are − 10.5 and − 7.9 kcal/mol; − 8.9 and − 7.8 kcal/mol; and − 9.1 and − 7.6 kcal/mol, respectively. Curcumin directly binds to the receptor binding domain (RBD) of viral S Protein. Molecular simulation study over a period of 100 ns further substantiates that such interaction within RBD site of S Protein occurs during 40–100 ns out of 100 ns simulation trajectory. Contrary to this, catechin binds with amino acid residues present near the RBD site of S Protein and causes fluctuation in the amino acid residues of the RBD and its near proximity. Both catechin and curcumin bind the interface of ‘RBD/ACE2-complex’ and intervene in causing fluctuation of the alpha helices and beta-strands of the protein complex. Protein–protein interaction studies in presence of curcumin or catechin also corroborate the above findings suggesting the efficacy of these two polyphenols in hindering the formation of S Protein-ACE2 complex. In conclusion, this computational study for the first time predicts the possibility of above two polyphenols for therapeutic strategy against SARS-CoV2.

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Protein-protein docking with large-scale backbone flexibility

10.1101/2021.02.22.432196 ◽

2021 ◽

Author(s):

Mateusz Kurcinski ◽

Sebastian Kmiecik ◽

Mateusz Zalewski ◽

Andrzej Kolinski

Keyword(s):

Binding Site ◽

Structure Prediction ◽

Large Scale ◽

Protein Complexes ◽

Complex Structure ◽

Protein Docking ◽

Coarse Grained ◽

Backbone Flexibility ◽

Docking Simulations ◽

Docking Protocol

AbstractStructure prediction of protein-protein complexes is one of the most critical challenges in computational structural biology. It is often difficult to predict the complex structure, even for relatively rigid proteins. Modeling significant structural flexibility in protein docking remains an unsolved problem. This work demonstrates a protein-protein docking protocol with enhanced sampling that accounts for large-scale backbone flexibility. The docking protocol starts from unbound x-ray structures and is not using any binding site information. In docking, one protein partner undergoes multiple fold rearrangements, rotations, and translations during docking simulations, while the other protein exhibits small backbone fluctuations. Including significant backbone flexibility during the search for the binding site has been made possible using the CABS coarse-grained protein model and Replica Exchange Monte Carlo dynamics. In our simulations, we obtained acceptable quality models for the set of 12 protein-protein complexes, while for selected cases, models were close to high accuracy.

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