Dataset Information

The Discovery of a Putative Allosteric Site in the SARS-CoV-2 Spike Protein Using an Integrated Structural/Dynamic Approach.

ABSTRACT: SARS-CoV-2 has caused the largest pandemic of the twenty-first century (COVID-19), threatening the life and economy of all countries in the world. The identification of novel therapies and vaccines that can mitigate or control this global health threat is among the most important challenges facing biomedical sciences. To construct a long-term strategy to fight both SARS-CoV-2 and other possible future threats from coronaviruses, it is critical to understand the molecular mechanisms underlying the virus action. The viral entry and associated infectivity stems from the formation of the SARS-CoV-2 spike protein complex with angiotensin-converting enzyme 2 (ACE2). The detection of putative allosteric sites on the viral spike protein molecule can be used to elucidate the molecular pathways that can be targeted with allosteric drugs to weaken the spike-ACE2 interaction and, thus, reduce viral infectivity. In this study, we present the results of the application of different computational methods aimed at detecting allosteric sites on the SARS-CoV-2 spike protein. The adopted tools consisted of the protein contact networks (PCNs), SEPAS (Affinity by Flexibility), and perturbation response scanning (PRS) based on elastic network modes. All of these methods were applied to the ACE2 complex with both the SARS-CoV2 and SARS-CoV spike proteins. All of the adopted analyses converged toward a specific region (allosteric modulation region [AMR]), present in both complexes and predicted to act as an allosteric site modulating the binding of the spike protein with ACE2. Preliminary results on hepcidin (a molecule with strong structural and sequence with AMR) indicated an inhibitory effect on the binding affinity of the spike protein toward the ACE2 protein.

SUBMITTER: Di Paola L

PROVIDER: S-EPMC7331933 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The Discovery of a Putative Allosteric Site in the SARS-CoV-2 Spike Protein Using an Integrated Structural/Dynamic Approach.

Di Paola Luisa L Hadi-Alijanvand Hamid H Song Xingyu X Hu Guang G Giuliani Alessandro A

Journal of proteome research 20200701 11

SARS-CoV-2 has caused the largest pandemic of the twenty-first century (COVID-19), threatening the life and economy of all countries in the world. The identification of novel therapies and vaccines that can mitigate or control this global health threat is among the most important challenges facing biomedical sciences. To construct a long-term strategy to fight both SARS-CoV-2 and other possible future threats from coronaviruses, it is critical to understand the molecular mechanisms underlying th ...[more]

PMID: 32551648

Similar Datasets

Project description:Structural and biochemical studies of the severe acute respiratory syndrome (SARS)-CoV-2 spike glycoproteins and complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes highlighting conformational plasticity of spike proteins and capacity for eliciting specific binding and broad neutralization responses. In this study, we used coevolutionary analysis, molecular simulations, and perturbation-based hierarchical network modeling of the SARS-CoV-2 spike protein complexes with a panel of antibodies targeting distinct epitopes to explore molecular mechanisms underlying binding-induced modulation of dynamics and allosteric signaling in the spike proteins. Through coevolutionary analysis of the SARS-CoV-2 spike proteins, we identified highly coevolving hotspots and functional clusters that enable a functional cross-talk between distant allosteric regions in the SARS-CoV-2 spike complexes with antibodies. Coarse-grained and all-atom molecular dynamics simulations combined with mutational sensitivity mapping and perturbation-based profiling of the SARS-CoV-2 receptor-binding domain (RBD) complexes with CR3022 and CB6 antibodies enabled a detailed validation of the proposed approach and an extensive quantitative comparison with the experimental structural and deep mutagenesis scanning data. By combining in silico mutational scanning, perturbation-based modeling, and network analysis of the SARS-CoV-2 spike trimer complexes with H014, S309, S2M11, and S2E12 antibodies, we demonstrated that antibodies can incur specific and functionally relevant changes by modulating allosteric propensities and collective dynamics of the SARS-CoV-2 spike proteins. The results provide a novel insight into regulatory mechanisms of SARS-CoV-2 S proteins showing that antibody-escaping mutations can preferentially target structurally adaptable energy hotspots and allosteric effector centers that control functional movements and allosteric communication in the complexes.

Dataset Information

The Discovery of a Putative Allosteric Site in the SARS-CoV-2 Spike Protein Using an Integrated Structural/Dynamic Approach.

Publications

The Discovery of a Putative Allosteric Site in the SARS-CoV-2 Spike Protein Using an Integrated Structural/Dynamic Approach.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets