Prediction and Evolution of the Molecular Fitness of SARS-CoV-2 Variants: Introducing SpikePro

Pucci, Fabrizio; Rooman, Marianne

doi:10.3390/v13050935

Cited by 30 publications

(22 citation statements)

References 67 publications

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“…We have demonstrated that, individually, some mutations may stabilize or destabilize the protein structure, since their occurrence triggers different effects on energy balances and potentially affects viral fitness. As shown by the result of our majority consensus analysis and demonstrated by Pucci and Rooman (2021) (138, 484, 614, 681, 845, and 1,176).…”

Section: Discussionsupporting

confidence: 52%

Molecular evolution and structural analyses of the spike glycoprotein from Brazilian SARS-CoV-2 genomes: the impact of the fixation of selected mutations

Ferrareze

Zimerman

Franceschi

et al. 2021

Preprint

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The COVID-19 pandemic caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached by July 2021 almost 200 million cases and more than 4 million deaths worldwide since its beginning in late 2019, leading to enhanced concern in the scientific community and the general population. One of the most important pieces of this host-pathogen interaction is the spike protein, which binds to the human Angiotensin-converting enzyme 2 (hACE2) cell receptor, mediates the membrane fusion and is the major target of neutralizing antibodies against SARS-CoV-2. The multiple amino acid substitutions observed in this region, specially in the Receptor Binding Domain (RBD), mainly after almost one year of its emergence (late 2020), have enhanced the hACE2 binding affinity and led to several modifications in the mechanisms of SARS-CoV-2 pathogenesis, improving the viral fitness and/or promoting immune evasion, with potential impact in the vaccine development. In this way, the present work aimed to evaluate the effect of positively selected mutations fixed in the Brazilian SARS-CoV-2 lineages and to check for mutational evidence of coevolution. Additionally, we evaluated the impact of selected mutations identified in some of the VOC and VOI lineages (C.37, B.1.1.7, P.1, and P.2) of Brazilian samples on the structural stability of the spike protein, as well as their possible association with more aggressive infection profiles by estimating the binding affinity in the RBD-hACE2 complex. We identified 48 sites under selective pressure in Brazilian spike sequences, 17 of them with the strongest evidence by the HyPhy tests, including VOC related mutation sites 138, 142, 222, 262, 484, 681, and 845, among others. The coevolutionary analysis identified a number of 28 coevolving sites that were found not to be conditionally independent, such as the couple E484K - N501Y from P.1 and B.1.351 lineages. Finally, the molecular dynamics and free energy estimates showed the structural stabilizing effect and the higher impact of E484K for the improvement of the binding affinity between the spike RBD and the hACE2 in P.1 and P.2 lineages, as well as the stabilizing and destabilizing effects for the positively selected sites.

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Section: Discussionsupporting

confidence: 52%

Molecular evolution and structural analyses of the spike glycoprotein from Brazilian SARS-CoV-2 genomes: the impact of the fixation of selected mutations

Ferrareze

Zimerman

Franceschi

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…In addition, with the right computational resources, the presented pipeline can be employed for building a library of all the possible RBD variants, which might be predicted based on solid evolutionary tools [ 114 – 116 ] and population genetics tools [ 117 , 118 ], for trying to understand which (and where) future spike variants will appear [ 2 , 5 , 16 ], to quickly predict their binding affinity for the different known ACE2 variants present in the world population (i.e., see https://gnomad.broadinstitute.org/gene/ENSG00000130234?dataset=exac ). Thus, it would be possible to early predict which RBD variants might be more dangerous for human health even before their appearance.…”

Section: Conclusion and Recommendationsmentioning

confidence: 99%

Modeling SARS-CoV-2 spike/ACE2 protein–protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context

Tragni

Laera

et al. 2022

EPMA Journal

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Aims The rapid spread of new SARS-CoV-2 variants has highlighted the crucial role played in the infection by mutations occurring at the SARS-CoV-2 spike receptor binding domain (RBD) in the interactions with the human ACE2 receptor. In this context, it urgently needs to develop new rapid tools for quickly predicting the affinity of ACE2 for the SARS-CoV-2 spike RBD protein variants to be used with the ongoing SARS-CoV-2 genomic sequencing activities in the clinics, aiming to gain clues about the transmissibility and virulence of new variants, to prevent new outbreaks and to quickly estimate the severity of the disease in the context of the 3PM. Methods In our study, we used a computational pipeline for calculating the interaction energies at the SARS-CoV-2 spike RBD/ACE2 protein–protein interface for a selected group of characterized infectious variants of concern/interest (VoC/VoI). By using our pipeline, we built 3D comparative models of the SARS-CoV-2 spike RBD/ACE2 protein complexes for the VoC B.1.1.7-United Kingdom (carrying the mutations of concern/interest N501Y, S494P, E484K at the RBD), P.1-Japan/Brazil (RBD mutations: K417T, E484K, N501Y), B.1.351-South Africa (RBD mutations: K417N, E484K, N501Y), B.1.427/B.1.429-California (RBD mutations: L452R), the B.1.141 (RBD mutations: N439K), and the recent B.1.617.1-India (RBD mutations: L452R; E484Q) and the B.1.620 (RBD mutations: S477N; E484K). Then, we used the obtained 3D comparative models of the SARS-CoV-2 spike RBD/ACE2 protein complexes for predicting the interaction energies at the protein–protein interface. Results Along SARS-CoV-2 mutation database screening and mutation localization analysis, it was ascertained that the most dangerous mutations at VoC/VoI spike proteins are located mainly at three regions of the SARS-CoV-2 spike “boat-shaped” receptor binding motif, on the RBD domain. Notably, the P.1 Japan/Brazil variant present three mutations, K417T, E484K, N501Y, located along the entire receptor binding motif, which apparently determines the highest interaction energy at the SARS-CoV-2 spike RBD/ACE2 protein–protein interface, among those calculated. Conversely, it was also observed that the replacement of a single acidic/hydrophilic residue with a basic residue (E484K or N439K) at the “stern” or “bow” regions, of the boat-shaped receptor binding motif on the RBD, appears to determine an interaction energy with ACE2 receptor higher than that observed with single mutations occurring at the “hull” region or with other multiple mutants. In addition, our pipeline allowed searching for ACE2 structurally related proteins, i.e., THOP1 and NLN, which deserve to be investigated for their possible involvement in interactions with the SARS-CoV-2 spike protein, in those tissues showing a low expression of ACE2, or as a novel receptor for future spike variants. A freely available web-tool for the in silico calculation of the interaction energy at the SARS-CoV-2 spike RBD/ACE2 prot...

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“…At present, it remains challenging to computationally predict the emergence of future clinically significant SARS-CoV-2 variants, but a couple of approaches have been developed to model the interaction between newly identified SARS-CoV-2 variants and their host and predict their infectivity. A computational pipeline “SpikePro”, consisting of three-step in silico mutagenesis experiments, calculates the stability of mutant spike protein, the binding affinity between mutant spike and human ACE2, and the binding affinity between mutant spike and neutralizing antibodies to predict viral fitness ( Pucci and Rooman, 2021 ). Another recently published work also established a neural network model that could predict binding affinity changes of spike mutations to human ACE2 ( Chen et al, 2021 ).…”

Section: Disease Predictionmentioning

confidence: 99%

Pandemic strategies with computational and structural biology against COVID-19: A retrospective

Lin

2022

Computational and Structural Biotechnology Journal

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The emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic, has dominated all aspects of life for the better part of 2020 and into 2021. Research studies on the virus and exploration of therapeutic and preventive strategies has been moving at rapid rates to control the pandemic. In the field of computational and structural biology, recent research strategies have used multiple disciplines to compile large datasets to uncover statistical correlations and significance, visualize and model proteins, perform molecular dynamics simulations, and employ the help of artificial intelligence and machine learning to harness computational processing power to further the research on COVID-19, including drug screening, drug design, vaccine development, prognosis prediction, and outbreak prediction. These recent developments should help us better understand the viral disease and develop the much-needed therapies and strategies for the management of COVID-19.

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Prediction and Evolution of the Molecular Fitness of SARS-CoV-2 Variants: Introducing SpikePro

Cited by 30 publications

References 67 publications

Molecular evolution and structural analyses of the spike glycoprotein from Brazilian SARS-CoV-2 genomes: the impact of the fixation of selected mutations

Molecular evolution and structural analyses of the spike glycoprotein from Brazilian SARS-CoV-2 genomes: the impact of the fixation of selected mutations

Modeling SARS-CoV-2 spike/ACE2 protein–protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context

Pandemic strategies with computational and structural biology against COVID-19: A retrospective

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