key: cord-0683542-vku3fmqa
authors: Alnomasy, Sultan F.
title: Virus-receptor interactions of SARS-CoV-2 spike receptor-binding domain and human neuropilin-1 b1 domain
date: 2021-04-09
journal: Saudi J Biol Sci
DOI: 10.1016/j.sjbs.2021.03.074
sha: 526549615c929db0cdc953fa513b06f90bedf871
doc_id: 683542
cord_uid: vku3fmqa

In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wahan, China and it causes disease which is known as COVID-19. This infection spreads everywhere in the global, and it leads to an enormous number of death among individuals. The mystery issue about SARS-CoV-2 that appears not have functions of a hemagglutinin and neuraminidase like other coronaviruses. Angiotensin-converting enzyme 2 (ACE2) is the main surface receptor for entering SARS-CoV-2 into the host cell. This entry process is mediated by binding SARS-CoV-2 spike receptor-binding domain (RBD) domain to ACE2. Recently, researchers discover a new receptor responsible for the SARS-CoV-2 entry which is neuropilin-1 (NRP1). So, this work provide afford a knowledge of how the interaction between SARS-CoV-2 spike RBD domain and NRP1 b1 domain is occurred. Understanding of the interaction would be very necessary for drug design.

COVID-19 is disease caused by new emerged virus known as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus is quickly spread to all world countries and causing high mortality and morbidity when compared to MERS-CoV and SARS-CoV (Datta et al., 2020) . (Farkash et al., 2020) .These cells are express angiotensin converting enzyme type 2 (ACE2) that facilitates SARS-CoV-2 entry (Harmer et al., 2002; Soler et al., 2013) . The entry of this virus into the host cell is mediated by binding of SARS-CoV-2 spike receptor-binding domain (RBD) to ACE2 (Robson, 2020) . This binding leads to the downregulation of ACE2 that may facilitate the progression of COVID-19 from slight to more severe illness such as huge stimulation of platelets and coagulation pathways (Datta et al., 2020) . ACE2 may play a critical role in COVID-19 progression. ACE2 is expressed in several tissues such as heart, intestine and kidney (Zhou et al., 2020) . SARS-CoV use its surface spike protein to mediate the entry into host cells. This virus comprises a RBD that specifically recognized by its receptor, ACE2 (F. Li et al., 2005; W. Li et al., 2003) . Besides ACE2 researchers found that neuropilin-1 (NRP1) plays as an alternative pathway for SARS-CoV-2 entry and also involved in the infection of SARS-CoV-2 (Cantuti- Castelvetri et al., 2020; Daly et al., 2020) . NRP1 is a transmembrane receptor and works as a co-receptor for many ligands (Guo et al., 2015; Roy et al., 2017) . It composes extracellular regions; CUB domains (a1 and a2), coagulation factor domains (b1 and b2), and a MAM domain (Guo & Vander Kooi, 2015) . Of these, SARS-CoV-2 spike protein can bind to the b1 domain of NRP1 (Cantuti-Castelvetri et al., 2020; Daly et al., 2020) . Based on these findings, there is no data about the virus-host interactions that identifying the potential binding sites of SARS-CoV-2 spike RBD on NRP1 b1 domain. In this work, an in silico analysis of interaction of SARS-CoV-2 spike RBD with b1 domain of NRP1 was generated for providing knowledge about the binding sites of this coronavirus spike protein on NRP1 b1 domain. So, this computational method would contribute in achieving the aim of understanding about the SARS-CoV-2-NRP1interactions.

The wild type of the SARS-CoV-2 genome corresponds to the NCBI reference sequence (NC_045512.2), isolated in December 2019 from a patient with COVID-19 in Wuhan, China (Lan et al., 2020) .

Structures of SARS-CoV-2 spike RBD domain and structure of the human neuropilin-1 b1 were downloaded from Protein Data Bank (PDB) (www.rcsb.org). The spike structure of SARS-CoV-2 with PDB code 6m0j (Lan et al., 2020) was used as the reference to align other structures of the protein to facilitate further analyses of the docking results. The structure 6m0j is provided as the complex between the spike RBD domain and ACE-2 (i.e., PDBcode_6m0j-ACE2) and without ACE-2 (i.e., PDB code_6m0j-noACE2, 6m0j:E). The structure of the human NRP1 b1 domain was found with PDB code_ 5JGQ. In the preparation process, we added the hydrogen atoms and optimized the hydrogen bond network with PROPKA (Olsson et al., 2011) considering pH = 7.

None of the ionizable residues required manual adjustment of protonation states. The selenomethionine residues were converted to methionines and all non-protein molecules were deleted (waters, ions, cofactors and ligands).

To perform docking studies, PDB files of 5JGQ and 6m0j:E were submitted to Cluspro 2.0 server (Kozakov et al., 2013; Kozakov et al., 2017; Vajda et al., 2017) . Cluspro 2.0 was generated several docking models, then ProQdock was used to check the quality of the docking models (Basu et al., 2016) .

The database of PDB was explored for the 3D structure of SARS-CoV-2 spike RBD, the accession number 6m0j:E was found. The structure of 6m0j:E was revealed by X-Ray diffraction (Lan et al., 2020) . After that, PDB database was also searched for the 3D structure of NRP1 b1 domain, PDB file with code 5JGQ was found. Therefore, work was carried out to identify binding sites of SARS-CoV-2 spike RBD on NRP1 b1 domain. Cluspro 2.0 was created several docking models. These models were ranked based on their quality score by ProQdock. The top-scored docking model was selected in this work (Fig 1A) . The score of modeling confidence was used to judge the reliability of this docking model, and its overall global quality score is 0.92520. This score showed that this docking has a more confident model. This docking model showed that there are potential sites of binding of SARS-CoV-2 spike RBD domain on NRP1 b1 domain (Fig 1B) . In this model, many locations of interaction were identified as potential binding sites for SARS-CoV-2 spike RBD domain on b1 domain of NRP1. GLN 280 , ASP 289 , TYR 322 , ARG 323 , TRP 325 , GLN 327 , ASP 329 , LYS 359 , ASP 361 residues were identified as potential binding sites on NRP1 b1 domain for SARS-CoV-2 spike RBD domain (Fig 1B) . Also, there is a contact between GLN 3 , ILE 8 , PHE 29 , ALA 30 of SARS-CoV-2 spike RBD domain and ARG 402 , ARG 405 , LYS 407 of NRP1 b1 domain (Fig 1B) .

This docking study showed several important binding sites for SARS-CoV-2 spike RBD domain on human host NRP1 b1 domain. These data could be contribute in reaching the goal for treatment development against SARS-CoV-2 through providing more information about binding sites of the interaction of SARS-CoV-2 spike RBD domain with human host NRP1 b1 domain.

Docking model of interaction of SARS-CoV-2 spike RBD with NRP1 b1 domain. The overall global quality score is 0.92520. This docking model was generated by Cluspro 2.0, then ProQdock was used to check its quality. This model was visualized by PyMOL1.3. (B) Binding site of SARS-CoV-2 spike RBD on NRP1 b1 domain. Residues of SARS-CoV-2 spike RBD on the Y-axis and NRP1 b1 domain residues on X-axis. Blue squares represents for residues that involves in interaction of SARS-CoV-2 spike RBD with NRP1 b1 domain.

The SARS-CoV-2 is causative agent for the COVID-19 that emerged in Wahan, China in December 2019 and leading to an uncontrollable global outbreak. COVID-19 is associated with severe respiratory illness, fever, and pneumonia (Lai et al., 2020) . The mechanism of SARS-CoV-2 entry into host has been extensively studied with ACE2 (Datta et al., 2020; Lan et al., 2020) .

Recently, scientists found that NRP1 is potential another pathway for SARS-CoV-2 entry and is implicated in the progression of COVID-19 (Cantuti-Castelvetri et al., 2020; Daly et al., 2020) .

The studying of the interaction of SARS-CoV-2 spike RBD domain with NRP1 b1 domain is conducted in this work due to there are limited studied about this interaction. So, docking study is carried out for this purpose. Binding sites of SARS-CoV-2 spike RBD domain with its NRP1 receptor that presents on surface with interacting amino acids; GLN 280 , ASP 289 , TYR 322 , ARG 323 , TRP 325 , GLN 327 , ASP 329 , LYS 359 , ASP 361 . Bound structure of SARS-CoV-2 spike RBD with NRP1 b1 domain is considered as target for drug discovery to treat SARS-CoV-2 infection.

The bioinformatics analyses indicated the possible binding specificity of SARS-CoV-2 spike RBD domain and NRP1 b1 domain. Data predict how the initial binding of SARS-CoV-2 spike RBD domain to NRP1 b1 domain may happen. These data are necessary for drug-design perspective.

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