{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T16:17:10Z","timestamp":1787674630722,"version":"build-2784847793"},"reference-count":92,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T00:00:00Z","timestamp":1694736000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006242","name":"Universiti Malaysia Sabah","doi-asserted-by":"publisher","award":["SDK0207-2020"],"award-info":[{"award-number":["SDK0207-2020"]}],"id":[{"id":"10.13039\/501100006242","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006242","name":"Universiti Malaysia Sabah","doi-asserted-by":"publisher","award":["GUG0524-2\/2020"],"award-info":[{"award-number":["GUG0524-2\/2020"]}],"id":[{"id":"10.13039\/501100006242","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>SARS-CoV-2, responsible for the COVID-19 pandemic, invades host cells via its spike protein, which includes critical binding regions, such as the receptor-binding domain (RBD), the S1\/S2 cleavage site, the S2 cleavage site, and heptad-repeat (HR) sections. Peptides targeting the RBD and HR1 inhibit binding to host ACE2 receptors and the formation of the fusion core. Other peptides target proteases, such as TMPRSS2 and cathepsin L, to prevent the cleavage of the S protein. However, research has largely ignored peptides targeting the S1\/S2 cleavage site. In this study, bioinformatics was used to investigate the binding of the S1\/S2 cleavage site to host proteases, including furin, trypsin, TMPRSS2, matriptase, cathepsin B, and cathepsin L. Peptides targeting the S1\/S2 site were designed by identifying binding residues. Peptides were docked to the S1\/S2 site using HADDOCK (High-Ambiguity-Driven protein\u2013protein DOCKing). Nine peptides with the lowest HADDOCK scores and strong binding affinities were selected, which was followed by molecular dynamics simulations (MDSs) for further investigation. Among these peptides, BR582 and BR599 stand out. They exhibited relatively high interaction energies with the S protein at \u22121004.769 \u00b1 21.2 kJ\/mol and \u22121040.334 \u00b1 24.1 kJ\/mol, respectively. It is noteworthy that the binding of these peptides to the S protein remained stable during the MDSs. In conclusion, this research highlights the potential of peptides targeting the S1\/S2 cleavage site as a means to prevent SARS-CoV-2 from entering cells, and contributes to the development of therapeutic interventions against COVID-19.<\/jats:p>","DOI":"10.3390\/v15091930","type":"journal-article","created":{"date-parts":[[2023,9,17]],"date-time":"2023-09-17T06:36:45Z","timestamp":1694932605000},"page":"1930","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["An In Silico Design of Peptides Targeting the S1\/S2 Cleavage Site of the SARS-CoV-2 Spike Protein"],"prefix":"10.3390","volume":"15","author":[{"given":"Chian","family":"Ho","sequence":"first","affiliation":[{"name":"Faculty of Science and Natural Resources, Universiti Malaysia Sabah, Kota Kinabalu 88400, Sabah, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan Fahmi Wan Mohamad","family":"Nazarie","sequence":"additional","affiliation":[{"name":"Faculty of Science and Natural Resources, Universiti Malaysia Sabah, Kota Kinabalu 88400, Sabah, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4280-0829","authenticated-orcid":false,"given":"Ping-Chin","family":"Lee","sequence":"additional","affiliation":[{"name":"Faculty of Science and Natural Resources, Universiti Malaysia Sabah, Kota Kinabalu 88400, Sabah, Malaysia"},{"name":"Biotechnology Research Institute, Universiti Malaysia Sabah, Kota Kinabalu 88400, Sabah, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1097\/JCMA.0000000000000270","article-title":"The outbreak of COVID-19","volume":"83","author":"Wu","year":"2020","journal-title":"J. Chin. Med. Assoc."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ng, J.W., Chong, E.T.J., Tan, Y.A., Lee, H.G., Chan, L.L., Lee, Q.Z., Saw, Y.T., Wong, Y., Bin Zakaria, A.A., and Amin, Z.B. (2022). Prevalence of Coronavirus Disease 2019 (COVID-19) in Different Clinical Stages before the National COVID-19 Vaccination Programme in Malaysia: A Systematic Review and Meta-Analysis. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph19042216"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/bs.aivir.2019.08.002","article-title":"Structural insights into coronavirus entry","volume":"105","author":"Tortorici","year":"2019","journal-title":"Adv. Virus Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5143","DOI":"10.1021\/acsnano.0c02857","article-title":"Computational design of ACE2-based peptide inhibitors of SARS-CoV-2","volume":"14","author":"Han","year":"2020","journal-title":"ACS Nano"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17038","DOI":"10.1016\/j.peptides.2020.170328","article-title":"In silico design of antiviral peptides targeting the spike protein of SARS-CoV-2","volume":"130","author":"Ling","year":"2020","journal-title":"Peptides"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100306","DOI":"10.1016\/j.jbc.2021.100306","article-title":"SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis","volume":"296","author":"Bayati","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41580-021-00418-x","article-title":"Mechanisms of SARS-CoV-2 entry into cells","volume":"23","author":"Jackson","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1080\/22221751.2022.2117098","article-title":"Spike mutations contributing to the altered entry preference of SARS-CoV-2 omicron BA.1 and BA.2","volume":"11","author":"Hu","year":"2022","journal-title":"Emerg. Microbes Infect."},{"key":"ref_9","first-page":"328","article-title":"A comparative overview of SARS-CoV-2 and its variants of concern","volume":"30","author":"Ahmad","year":"2022","journal-title":"Infez. Med."},{"key":"ref_10","first-page":"162","article-title":"SARS-CoV-2 variant biology: Immune escape, transmission and fitness","volume":"21","author":"Carabelli","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_11","unstructured":"(2023, May 19). Coronavirus (COVID-19)|Drugs, Available online: https:\/\/www.fda.gov\/drugs\/emergency-preparedness-drugs\/coronavirus-covid-19-drugs."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10003","DOI":"10.7189\/jogh.11.10003","article-title":"Current COVID-19 treatments: Rapid review of the literature","volume":"11","author":"Dong","year":"2021","journal-title":"J. Glob. Health."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101489","DOI":"10.1016\/j.eclinm.2022.101489","article-title":"Baricitinib in hospitalized patients with COVID-19: A meta-analysis of randomized controlled trials","volume":"49","author":"Selvaraj","year":"2022","journal-title":"EClinicalMedicine."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1126\/science.abf9302","article-title":"Prospective mapping of viral mutations that escape antibodies used to treat COVID-19","volume":"371","author":"Starr","year":"2021","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"830527","DOI":"10.3389\/fimmu.2021.830527","article-title":"Omicron: A Heavily Mutated SARS-CoV-2 Variant Exhibits Stronger Binding to ACE2 and Potently Escapes Approved COVID-19 Therapeutic Antibodies","volume":"12","author":"Shah","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e2200592119","DOI":"10.1073\/pnas.2200592119","article-title":"Omicron mutations enhance infectivity and reduce antibody neutralization of SARS-CoV-2 virus-like particles","volume":"119","author":"Syed","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1038\/s41564-022-01254-1","article-title":"Emergence of SARS-CoV-2 escape mutations during Bamlanivimab therapy in a phase II randomized clinical trial","volume":"7","author":"Choudhary","year":"2022","journal-title":"Nat. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12929-017-0328-x","article-title":"Evaluation of The Use of Therapeutic Peptides for Cancer Treatment","volume":"24","author":"Marqus","year":"2017","journal-title":"J. Biomed. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/cbdd.12055","article-title":"The Future of Peptide-Based Drugs","volume":"81","author":"Craik","year":"2013","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.drudis.2014.10.003","article-title":"Peptide Therapeutics: Current Status and Future Directions","volume":"20","author":"Fosgerau","year":"2015","journal-title":"Drug Discov. Today"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.addr.2020.11.007","article-title":"Peptide and peptide-based inhibitors of SARS-CoV-2 entry","volume":"167","author":"Kirchhoff","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ho, C., and Lee, P.-C. (2022). COVID-19 Treatment\u2014Current Status, Advances, and Gap. Pathogens, 11.","DOI":"10.3390\/pathogens11101201"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"101212","DOI":"10.1016\/j.isci.2020.101212","article-title":"Proteolytic cleavage of the SARS-CoV-2 spike protein and the role of the novel S1\/S2 site","volume":"23","author":"Jaimes","year":"2020","journal-title":"iScience"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S0968-0004(98)01254-7","article-title":"Catalytic triads and their relatives","volume":"23","author":"Dodson","year":"1998","journal-title":"Trends Biochem. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"D506","DOI":"10.1093\/nar\/gky1049","article-title":"UniProt: A worldwide hub of protein knowledge","volume":"47","author":"Bateman","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cell.2020.02.058","article-title":"Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein","volume":"181","author":"Walls","year":"2020","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/pro.3730","article-title":"RCSB Protein Data Bank: Enabling biomedical research and drug discovery","volume":"29","author":"Goodsell","year":"2020","journal-title":"Protein Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: Homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e202000786","DOI":"10.26508\/lsa.202000786","article-title":"TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells","volume":"3","author":"Bestle","year":"2020","journal-title":"Life Sci. Alliance"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1021\/acsinfecdis.0c00701","article-title":"Proteolytic Activation of SARS-CoV-2 Spike at the S1\/S2 Boundary: Potential Role of Proteases beyond Furin","volume":"7","author":"Tang","year":"2021","journal-title":"ACS Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1021\/cb500087x","article-title":"X-ray structures of human furin in complex with competitive inhibitors","volume":"9","author":"Dahms","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4115","DOI":"10.1074\/jbc.M708268200","article-title":"Structural basis for accelerated cleavage of bovine pancreatic trypsin inhibitor (BPTI) by human mesotrypsin","volume":"283","author":"Salameh","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11155","DOI":"10.1074\/jbc.M113.454611","article-title":"Crystal structures of matriptase in complex with its inhibitor hepatocyte growth factor activator inhibitor-1","volume":"288","author":"Zhao","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1021\/acs.jmedchem.7b01430","article-title":"Discovery of Peptidomimetic Antibody-Drug Conjugate Linkers with Enhanced Protease Specificity","volume":"61","author":"Wei","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1002\/anie.201006781","article-title":"Systematic Investigation of Halogen Bonding in Protein\u2013Ligand Interactions","volume":"50","author":"Hardegger","year":"2011","journal-title":"Angew Chem. Int. Ed."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1016\/j.bpj.2011.10.024","article-title":"Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization","volume":"101","author":"Xu","year":"2011","journal-title":"Biophys. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.jmb.2015.09.014","article-title":"The HADDOCK2.2 webserver: User-friendly integrative modeling of biomolecular complexes","volume":"428","author":"Rodrigues","year":"2016","journal-title":"J. Mol. Biol."},{"key":"ref_38","unstructured":"(2019, September 05). PyMOL. Available online: http:\/\/www.pymol.org\/pymol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera-a visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1093\/nar\/gkw329","article-title":"PEP-FOLD3: Faster de novo structure prediction for linear peptides in solution and in complex","volume":"44","author":"Lamiable","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"W406","DOI":"10.1093\/nar\/gkw336","article-title":"3Drefine: An interactive web server for efficient protein structure refinement","volume":"44","author":"Bhattacharya","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3676","DOI":"10.1093\/bioinformatics\/btw514","article-title":"PRODIGY: A web-server for predicting the binding affinity in protein-protein complexes","volume":"32","author":"Xue","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Gupta, S., Kapoor, P., Chaudhary, K., Gautam, A., Kumar, R., and Raghava, G.P.S. (2013). In Silico approach for predicting toxicity of peptides and proteins. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073957"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Walker, J.M. (2005). The Proteomics Protocols Handbook, Humana Press Inc.","DOI":"10.1385\/1592598900"},{"key":"ref_45","unstructured":"(2022, July 06). PepSMI: Convert Peptide to SMILES String. Available online: https:\/\/www.novoprolabs.com\/tools\/convert-peptide-to-smiles-string."},{"key":"ref_46","unstructured":"(2022, July 06). Pharmacokinetic Properties. Available online: https:\/\/biosig.lab.uq.edu.au\/pkcsm\/prediction."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1021\/ct300400x","article-title":"Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone \u03c6, \u03c8 and side-chain \u03c71 and \u03c72 Dihedral Angles","volume":"8","author":"Best","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"ref_48","unstructured":"Lindahl, E., Abraham, M.J., Hess, B., and van der Spoel, D. (2020). GROMACS, version 2020.1 Manual, Zenodo."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/0010-4655(95)00042-E","article-title":"GROMACS: A message-passing parallel molecular dynamics implementation","volume":"91","author":"Berendsen","year":"1995","journal-title":"Comp. Phys. Comm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1021\/acs.jcim.1c01451","article-title":"Omicron variant (B.1.1.529): Infectivity, vaccine breakthrough, and antibody resistance","volume":"62","author":"Chen","year":"2022","journal-title":"J. Chem. Inf. Model."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4958","DOI":"10.1038\/s41467-022-32665-7","article-title":"Omicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape","volume":"13","author":"Zhao","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1093\/bioinformatics\/btz828","article-title":"QMEANDisCo\u2014Distance constraints applied on model quality estimation","volume":"36","author":"Studer","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1093\/bioinformatics\/btq662","article-title":"Toward the estimation of the absolute quality of individual protein structure models","volume":"27","author":"Benkert","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/S0006-3495(03)74553-6","article-title":"Molecular dynamics simulation of dimeric and monomeric forms of human prion protein: Insight into dynamics and properties","volume":"85","author":"Sekijima","year":"2003","journal-title":"Biophys. J."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kalathiya, U., Padariya, M., Mayordomo, M., Lisowska, M., Nicholson, J., Singh, A., Baginski, M., Fahraeus, R., Carragher, N., and Ball, K. (2020). Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site. J. Clin. Med., 9.","DOI":"10.20944\/preprints202004.0439.v1"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4659","DOI":"10.1038\/s41598-021-84053-8","article-title":"Structural insights into SARS-CoV-2 spike protein and its natural mutants found in Mexican population","volume":"11","author":"Bello","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s10822-020-00356-4","article-title":"Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein","volume":"35","author":"Deganutti","year":"2021","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1107\/S0021889892009944","article-title":"PROCHECK: A program to check the stereochemical quality of protein structures","volume":"26","author":"Laskowski","year":"1993","journal-title":"J. Appl. Crystallogr."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"W407","DOI":"10.1093\/nar\/gkm290","article-title":"ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins","volume":"35","author":"Wiederstein","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1007\/978-1-4939-7000-1_24","article-title":"Stereochemistry and Validation of Macromolecular Structures","volume":"1607","author":"Wlodawer","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1107\/97809553602060000882","article-title":"PROCHECK: Validation of protein-structure coordinates","volume":"F","author":"Laskowski","year":"2012","journal-title":"Int. Tables Crystallogr."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s40781-015-0077-x","article-title":"In silico characterization, homology modelling and structure-based functional annotation of blunt snout bream (Megalobrama amblycephala) Hsp70 and Hsc70 proteins","volume":"57","author":"Tran","year":"2015","journal-title":"J. Anim. Sci. Technol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Sonawane, K., Barale, S.S., Dhanavade, M.J., Waghmare, S.R., Nadaf, N.H., Kamble, S.A., Mohammed, A.A., Makandar, A.M., Fandilolu, P.M., and Dound, A.S. (2020). Homology modeling and docking studies of TMPRSS2 with experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride to control SARS-Coronavirus-2. ChemRxiv.","DOI":"10.26434\/chemrxiv.12162360"},{"key":"ref_64","unstructured":"(2022, November 08). PROCHECK Operating Manual. Available online: http:\/\/www.csb.yale.edu\/userguides\/datamanip\/procheck\/manual\/manappe.html."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Ho, B.K., and Brasseur, R. (2005). The Ramachandran plots of glycine and pre-proline. BMC Struct. Biol., 5.","DOI":"10.1186\/1472-6807-5-14"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Mansbach, R.A., Chakraborty, S., Travers, T., and Gnanakaran, S. (2020). Graph-Directed Approach for Downselecting Toxins for Experimental Structure Determination. Mar. Drugs., 18.","DOI":"10.3390\/md18050256"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"13276","DOI":"10.1073\/pnas.1811364115","article-title":"Experimental accuracy in protein structure refinement via molecular dynamics simulations","volume":"115","author":"Heo","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1074\/mcp.M000051-MCP201","article-title":"Building macromolecular assemblies by information-driven docking: Introducing the haddock multibody docking server","volume":"9","author":"Karaca","year":"2010","journal-title":"Mol. Cell Proteomics."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1021\/ja026939x","article-title":"HADDOCK: A protein-protein docking approach based on biochemical or biophysical information","volume":"125","author":"Dominguez","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1089\/cmb.2010.0123","article-title":"Finding nearly optimal GDT scores","volume":"18","author":"Li","year":"2011","journal-title":"J. Comput. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Han, X., Li, L., and Lu, Y. (2019). Selecting near-native protein structures from predicted decoy sets using ordered graphlet degree similarity. Genes, 10.","DOI":"10.3390\/genes10020132"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3370","DOI":"10.1093\/nar\/gkg571","article-title":"LGA: A method for finding 3D similarities in protein structures","volume":"31","author":"Zemla","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Carlsen, M., Koehl, P., and R\u00f8gen, P. (2014). On the importance of the distance measures used to train and test knowledge-based potentials for proteins. PLoS ONE., 9.","DOI":"10.1371\/journal.pone.0109335"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Chang, K.Y., and Yang, J.R. (2013). Analysis and prediction of highly effective antiviral peptides based on random forests. PloS ONE., 8.","DOI":"10.1371\/journal.pone.0070166"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s40035-015-0041-1","article-title":"The endosomal-lysosomal system: From acidification and cargo sorting to neurodegeneration","volume":"4","author":"Hu","year":"2015","journal-title":"Transl. Neurodegener."},{"key":"ref_76","first-page":"25","article-title":"Modulating lysosomal pH: A molecular and nanoscale materials design perspective","volume":"2","author":"Zeng","year":"2020","journal-title":"J. Life Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/0968-0004(89)90180-1","article-title":"How are substrates recognized by the ubiquitin-mediated proteolytic system?","volume":"14","author":"Ciechanover","year":"1989","journal-title":"Trends Biochem. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: Predicting small molecule pharmacokinetic and toxicity properties using graph-based signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/j.neuron.2018.08.011","article-title":"Molecular Dynamics Simulation for All","volume":"99","author":"Hollingsworth","year":"2018","journal-title":"Neuron."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"34984","DOI":"10.1038\/srep34984","article-title":"Structural insights into conformational stability of both wild-type and mutant EZH2 receptor","volume":"6","author":"Aier","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Ni, D., Song, K., Zhang, J., and Lu, S.Y. (2017). Molecular dynamics simulations and dynamic network analysis reveal the allosteric unbinding of monobody to H-Ras triggered by R135K mutation. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18112249"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/978-1-62703-658-0_11","article-title":"Principal component analysis: A method for determining the essential dynamics of proteins","volume":"1084","author":"David","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"031910","DOI":"10.1103\/PhysRevE.65.031910","article-title":"Convergence of sampling in protein simulations","volume":"65","author":"Hess","year":"2002","journal-title":"Phys. Rev. E. Stat. Nonlin. Soft Matter Phys."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1002\/jcc.21787","article-title":"MDAnalysis: A toolkit for the analysis of molecular dynamics simulations","volume":"32","author":"Denning","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Gowers, R.J., Linke, M., Barnoud, J., Reddy, T.J.E., Melo, M.N., Seyler, S.L., Doma\u0144ski, J., Dotson, D.L., Buchoux, S., and Kenney, I.M. (2016, January 11). MDAnalysis: A Python Package for the Rapid Analysis of Molecular Dynamics Simulations. Proceedings of the 15th Python in Science Conference, Austin, TX, USA.","DOI":"10.25080\/Majora-629e541a-00e"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"14991","DOI":"10.1038\/s41598-020-71748-7","article-title":"Analysis of the SARS-CoV-2 spike protein glycan shield reveals implications for immune recognition","volume":"10","author":"Grant","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"629873","DOI":"10.3389\/fmolb.2021.629873","article-title":"Glycans of SARS-CoV-2 Spike Protein in Virus Infection and Antibody Production","volume":"8","author":"Zhao","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/s41586-020-2349-y","article-title":"Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody","volume":"583","author":"Pinto","year":"2020","journal-title":"Nature"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1126\/science.abb9983","article-title":"Site-specific glycan analysis of the SARS-CoV-2 spike","volume":"369","author":"Watanabe","year":"2020","journal-title":"Science"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/s41392-021-00809-8","article-title":"The glycosylation in SARS-CoV-2 and its receptor ACE2","volume":"6","author":"Gong","year":"2021","journal-title":"Sig. Transduct. Target. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e2109905118","DOI":"10.1073\/pnas.2109905118","article-title":"Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation","volume":"118","author":"Zhang","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/0959-440X(95)80015-S","article-title":"Protein-peptide interactions","volume":"5","author":"Stanfield","year":"1995","journal-title":"Curr. Opin. Struct. Biol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/9\/1930\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:51:42Z","timestamp":1760129502000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/9\/1930"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,15]]},"references-count":92,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["v15091930"],"URL":"https:\/\/doi.org\/10.3390\/v15091930","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,15]]}}}