{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T07:36:32Z","timestamp":1779348992035,"version":"3.51.4"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T00:00:00Z","timestamp":1651190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korea Disease Control and Prevention Agency Grant","award":["6300-6331-301"],"award-info":[{"award-number":["6300-6331-301"]}]},{"name":"Korea Disease Control and Prevention Agency Grant","award":["NRF2020R1A2C100691511"],"award-info":[{"award-number":["NRF2020R1A2C100691511"]}]},{"name":"Ministry of Science, ICT and Future Planning","award":["6300-6331-301"],"award-info":[{"award-number":["6300-6331-301"]}]},{"name":"Ministry of Science, ICT and Future Planning","award":["NRF2020R1A2C100691511"],"award-info":[{"award-number":["NRF2020R1A2C100691511"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused the Coronavirus Disease (COVID-19) pandemic worldwide. The spike protein in SARS-CoV-2 fuses with and invades cells in the host respiratory system by binding to angiotensin-converting enzyme 2 (ACE2). The spike protein, however, undergoes continuous mutation from a D614G single mutant to an omicron variant, including multiple mutants. In this study, variants, including multiple mutants (double, triple mutants, B.1.620, delta, alpha, delta_E484Q, mu, and omicron) were investigated in patients. The 3D structure of the full-length spike protein was used in conformational analysis depending on the SARS-CoV-2 variants. The structural stability of the variant types was analyzed based on the distance between the receptor-binding domain (RBD) of each chain in the spike protein and the binding free energy between the spike protein and bound ACE2 in the one-, two-, and three-open-complex forms using molecular dynamics (MD) simulation. Omicron variants, the most prevalent in the recent history of the global pandemic, which consist of 32 mutations, showed higher stability in all open-complex forms compared with that of the wild type and other variants. We suggest that the conformational stability of the spike protein is the one of the important determinants for the differences in viral infectivity among variants, including multiple mutants.<\/jats:p>","DOI":"10.3390\/ijms23094956","type":"journal-article","created":{"date-parts":[[2022,4,30]],"date-time":"2022-04-30T05:44:07Z","timestamp":1651297447000},"page":"4956","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Molecular Dynamics Studies on the Structural Stability Prediction of SARS-CoV-2 Variants Including Multiple Mutants"],"prefix":"10.3390","volume":"23","author":[{"given":"Kwang-Eun","family":"Choi","sequence":"first","affiliation":[{"name":"Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8240-0395","authenticated-orcid":false,"given":"Jeong-Min","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Emerging Infectious Diseases, Bureau of Infectious Disease Diagnosis Control, Korea Disease Control and Prevention Agency, 187 Osongsaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju-si 28159, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jee Eun","family":"Rhee","sequence":"additional","affiliation":[{"name":"Division of Emerging Infectious Diseases, Bureau of Infectious Disease Diagnosis Control, Korea Disease Control and Prevention Agency, 187 Osongsaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju-si 28159, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ae Kyung","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Emerging Infectious Diseases, Bureau of Infectious Disease Diagnosis Control, Korea Disease Control and Prevention Agency, 187 Osongsaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju-si 28159, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun-Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Emerging Infectious Diseases, Bureau of Infectious Disease Diagnosis Control, Korea Disease Control and Prevention Agency, 187 Osongsaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju-si 28159, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheon Kwon","family":"Yoo","sequence":"additional","affiliation":[{"name":"Bureau of Infectious Disease Diagnosis Control, Korea Disease Control and Prevention Agency, 187 Osongsaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju-si 28159, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nam Sook","family":"Kang","sequence":"additional","affiliation":[{"name":"Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/s41401-020-0485-4","article-title":"Structural and functional properties of SARS-CoV-2 spike protein: Potential antivirus drug development for COVID-19","volume":"41","author":"Huang","year":"2020","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"106054","DOI":"10.1016\/j.ijantimicag.2020.106054","article-title":"Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): A global pandemic and treatment strategies","volume":"56","author":"Sharma","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sivakumar, B., and Deepthi, B. (2022). Complexity of COVID-19 Dynamics. Entropy, 24.","DOI":"10.3390\/e24010050"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.3389\/fimmu.2020.576622","article-title":"The SARS-CoV-2 spike glycoprotein biosynthesis, structure, function, and antigenicity: Implications for the design of spike-based vaccine immunogens","volume":"11","author":"Duan","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Yadav, R., Chaudhary, J.K., Jain, N., Chaudhary, P.K., Khanra, S., Dhamija, P., Sharma, A., Kumar, A., and Handu, S. (2021). Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19. Cells, 10.","DOI":"10.3390\/cells10040821"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"102115","DOI":"10.1016\/j.scr.2020.102115","article-title":"Furin cleavage sites naturally occur in coronaviruses","volume":"50","author":"Wu","year":"2021","journal-title":"Stem Cell Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1111\/all.14429","article-title":"Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors","volume":"75","author":"Radzikowska","year":"2020","journal-title":"Allergy"},{"key":"ref_8","first-page":"43","article-title":"Distant residues modulate conformational opening in SARS-CoV-2 spike protein","volume":"118","author":"Ray","year":"2021","journal-title":"BioRxiv"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"583523","DOI":"10.3389\/fmolb.2020.583523","article-title":"Investigation of the effect of temperature on the structure of SARS-CoV-2 Spike Protein by Molecular Dynamics Simulations","volume":"7","author":"Rath","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Hozhabri, H., Piceci Sparascio, F., Sohrabi, H., Mousavifar, L., Roy, R., Scribano, D., De Luca, A., Ambrosi, C., and Sarshar, M. (2020). The global emergency of novel coronavirus (SARS-CoV-2): An update of the current status and forecasting. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17165648"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Piplani, S., Singh, P.K., Winkler, D.A., and Petrovsky, N. (2020). In silico comparison of spike protein-ACE2 binding affinities across species; significance for the possible origin of the SARS-CoV-2 virus. arXiv.","DOI":"10.1038\/s41598-021-92388-5"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"18847","DOI":"10.1038\/s41598-021-96950-z","article-title":"Neutral evolution test of the spike protein of SARS-CoV-2 and its implications in the binding to ACE2","volume":"11","author":"Zamudio","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"789","DOI":"10.24272\/j.issn.2095-8137.2021.343","article-title":"Emerging SARS-CoV-2 B. 1.621\/Mu variant is prominently resistant to inactivated vaccine-elicited antibodies","volume":"42","author":"Xie","year":"2021","journal-title":"Zool. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1002\/mco2.110","article-title":"SARS-CoV-2 Omicron variant: Characteristics and prevention","volume":"2","author":"He","year":"2021","journal-title":"MedComm"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"751778","DOI":"10.3389\/fimmu.2021.751778","article-title":"The Global Epidemic of the SARS-CoV-2 Delta Variant, Key Spike Mutations and Immune Escape","volume":"12","author":"Tian","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Choi, K.-E., Kim, J.-M., Rhee, J., Park, A.K., Kim, E.-J., and Kang, N.S. (2021). Molecular Dynamics Studies on the Structural Characteristics for the Stability Prediction of SARS-CoV-2. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168714"},{"key":"ref_17","first-page":"90","article-title":"Unravelling the molecular interactions between the SARS-CoV-2 RBD spike protein and various specific monoclonal antibodies","volume":"193","author":"Alsina","year":"2021","journal-title":"Biochimie"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-71188-3","article-title":"Dynamics of the ACE2\u2013SARS-CoV-2\/SARS-CoV spike protein interface reveal unique mechanisms","volume":"10","author":"Ali","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Nelson, G., Buzko, O., Bassett, A., Spilman, P., Niazi, K., Rabizadeh, S., and Soon-Shiong, P. (2020). Millisecond-scale molecular dynamics simulation of spike RBD structure reveals evolutionary adaption of SARS-CoV-2 to stably bind ACE2. bioRxiv.","DOI":"10.1101\/2020.12.11.422055"},{"key":"ref_20","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_21","doi-asserted-by":"crossref","unstructured":"Peng, C., Zhu, Z., Shi, Y., Wang, X., Mu, K., Yang, Y., Zhang, X., and Xu, Z. (2021). Exploring the binding mechanism and accessible angle of SARS-CoV-2 spike and ACE2 by molecular dynamics simulation and free energy calculation. ChemRxiv.","DOI":"10.26434\/chemrxiv.11877492.v1"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.cell.2020.06.043","article-title":"Tracking changes in SARS-CoV-2 spike: Evidence that D614G increases infectivity of the COVID-19 virus","volume":"182","author":"Korber","year":"2020","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"109292","DOI":"10.1016\/j.celrep.2021.109292","article-title":"Recurrent emergence of SARS-CoV-2 spike deletion H69\/V70 and its role in the Alpha variant B. 1.1. 7","volume":"35","author":"Meng","year":"2021","journal-title":"Cell Rep."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hamill, V., Noll, L., Lu, N., Tsui, W.N.T., Porter, E.P., Gray, M., Sebhatu, T., Goerl, K., Brown, S., and Palinski, R. (2021). Molecular detection of SARS-CoV-2 strains and differentiation of Delta variant strains. Transbound. Emerg. Dis., ahead of print.","DOI":"10.1111\/tbed.14443"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Miner, J.C., Lappala, A., Fenimore, P.W., Fischer, W.M., McMahon, B.H., Hengartner, N.W., Sanbonmatsu, K.Y., and Tung, C.-S. (2021). Modeling the Influenza A NP-vRNA-Polymerase Complex in Atomic Detail. Biomolecules, 11.","DOI":"10.3390\/biom11010124"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12985-021-01526-y","article-title":"Precision therapeutic targets for COVID-19","volume":"18","author":"Krumm","year":"2021","journal-title":"Virol. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"694347","DOI":"10.3389\/fmedt.2021.694347","article-title":"Up state of the SARS-CoV-2 spike homotrimer favors an increased virulence for new variants","volume":"3","author":"Giron","year":"2021","journal-title":"Front. Med. Technol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/s41579-021-00573-0","article-title":"SARS-CoV-2 variants, spike mutations and immune escape","volume":"19","author":"Harvey","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_29","first-page":"1","article-title":"SARS-CoV-2 Omicron strain exhibits potent capabilities for immune evasion and viral entrance","volume":"6","author":"Zhang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.bbrc.2021.12.082","article-title":"Structural modeling of Omicron spike protein and its complex with human ACE-2 receptor: Molecular basis for high transmissibility of the virus","volume":"592","author":"Koleya","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Socher, E., Heger, L., Paulsen, F., Zunke, F., and Arnold, P. (2022). Molecular dynamics simulations of the delta and omicron SARS-CoV-2 spike\u2013ACE2 complexes reveal distinct changes between both variants. Comput. Struct. Biotechnol. J., ahead of print.","DOI":"10.21203\/rs.3.rs-1228784\/v1"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3","DOI":"10.24171\/j.phrp.2020.11.1.02","article-title":"Identification of coronavirus isolated from a patient in Korea with COVID-19","volume":"11","author":"Kim","year":"2020","journal-title":"Osong Public Health Res. Perspect."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"37","DOI":"10.24171\/j.phrp.2021.12.1.06","article-title":"Genomic surveillance of SARS-CoV-2: Distribution of clades in the Republic of Korea in 2020","volume":"12","author":"Park","year":"2021","journal-title":"Osong Public Health Res. Perspect."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Socher, E., Conrad, M., Heger, L., Paulsen, F., Sticht, H., Zunke, F., and Arnold, P. (2021). Mutations in the B. 1.1. 7 SARS-CoV-2 spike protein reduce receptor-binding affinity and induce a flexible link to the fusion peptide. Biomedicines, 9.","DOI":"10.1101\/2021.04.06.438584"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1021\/ct900549r","article-title":"Implementation of the CHARMM force field in GROMACS: Analysis of protein stability effects from correction maps, virtual interaction sites, and water models","volume":"6","author":"Bjelkmar","year":"2010","journal-title":"J. Chem. Theory Comput."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: An N log (N) method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1021\/ci500020m","article-title":"g_mmpbsa\u2014A GROMACS tool for high-throughput MM-PBSA calculations","volume":"54","author":"Kumari","year":"2014","journal-title":"J. Chem. Inf. Modeling"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/4956\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:04:15Z","timestamp":1760137455000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/4956"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,29]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23094956"],"URL":"https:\/\/doi.org\/10.3390\/ijms23094956","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,29]]}}}