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Evolutionary and Structural Studies of NCoV and SARS CoV-Spike proteins and their association with ACE2 Receptor

ABSTRACT: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)/Novel Corona Virus Disease-19 (nCOVID-19)/COVID-19 has only been discovered recently, and so our understanding of the disease epidemiology is continuously evolving. WHO has declared it a worldwide pandemic with high morbidity and significant mortality, hence it has been announced as the global health and wealth emergency. At present there is no any specific therapy available to fight against this virus, hence the drug repositioning is the most challenging to entire scientific community. The aim of this study is to determine the mutation(s) in the sequence of the spike protein, which plays a significant role in transmission from human to human. By using bioinformatics approach first we analyzed spike protein sequence of four nearest coronavirus family that include COVID-19, bat coronavirus RaTG13, pangolian coronavirus and SARS CoV, to determine phylogenetic distance between them. The homology modeling of COVID-19 spike protein has been done by iTASSER. and the protein-protein docking with human receptor ACE2 by Frodock web based docking tool showing the less binding energy of COVID-19 (?12.7 kcal/mol) in comparison with SARS CoV (10.3 kcal/mol). Further, the superimposed structure of COVID-19 and SARS CoV viruses has been performed to find the mutational site in association with human ACE2 protein. The extensive and detailed computational analyses approaches help to identify conserved region of COVID-19 and SARS CoV. Hence, our present data might help to identify potential target site and to develop antiviral drugs/vaccine to combat this pandemic.

SUBMITTER: Kumar A

PROVIDER: S-EPMC7677609 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Project description:MOTIVATION:The recent emergence of the novel SARS-coronavirus 2 (SARS-CoV-2) and its international spread pose a global health emergency. The spike (S) glycoprotein binds ACE2 and promotes SARS-CoV-2 entry into host cells. The trimeric S protein binds the receptor using the receptor-binding domain (RBD) causing conformational changes in S protein that allow priming by host cell proteases. Unraveling the dynamic structural features used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal novel therapeutic targets. Using structures determined by X-ray crystallography and cryo-EM, we performed structural analysis and atomic comparisons of the different conformational states adopted by the SARS-CoV-2-RBD. RESULTS:Here, we determined the key structural components induced by the receptor and characterized their intramolecular interactions. We show that ?-helix (polyproline-II) is a predominant structure in the binding interface and in facilitating the conversion to the active form of the S protein. We demonstrate a series of conversions between switch-like ?-helix and ?-strand, and conformational variations in a set of short ?-helices which affect the hinge region. These conformational changes lead to an alternating pattern in conserved disulfide bond configurations positioned at the hinge, indicating a possible disulfide exchange, an important allosteric switch implicated in viral entry of various viruses, including HIV and murine coronavirus. The structural information presented herein enables to inspect and understand the important dynamic features of SARS-CoV-2-RBD and propose a novel potential therapeutic strategy to block viral entry. Overall, this study provides guidance for the design and optimization of structure-based intervention strategies that target SARS-CoV-2. AVAILABILITY:We have implemented the proposed methods in an R package freely available at https://github.com/Grantlab/bio3d. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

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Evolutionary and Structural Studies of NCoV and SARS CoV-Spike proteins and their association with ACE2 Receptor

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