{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T21:51:50Z","timestamp":1788472310962,"version":"build-2803163510"},"reference-count":92,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T00:00:00Z","timestamp":1643155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institute of Theoretical and Experimental Biophysics","award":["075-00381-21-00"],"award-info":[{"award-number":["075-00381-21-00"]}]},{"name":"G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences","award":["0077-2019-0033"],"award-info":[{"award-number":["0077-2019-0033"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The entry of the SARS-CoV-2, a causative agent of COVID-19, into human host cells is mediated by the SARS-CoV-2 spike (S) glycoprotein, which critically depends on the formation of complexes involving the spike protein receptor-binding domain (RBD) and the human cellular membrane receptor angiotensin-converting enzyme 2 (hACE2). Using classical site density functional theory (SDFT) and structural bioinformatics methods, we investigate binding and conformational properties of these complexes and study the overlooked role of water-mediated interactions. Analysis of the three-dimensional reference interaction site model (3DRISM) of SDFT indicates that water mediated interactions in the form of additional water bridges strongly increases the binding between SARS-CoV-2 spike protein and hACE2 compared to SARS-CoV-1-hACE2 complex. By analyzing structures of SARS-CoV-2 and SARS-CoV-1, we find that the homotrimer SARS-CoV-2 S receptor-binding domain (RBD) has expanded in size, indicating large conformational change relative to SARS-CoV-1 S protein. Protomer with the up-conformational form of RBD, which binds with hACE2, exhibits stronger intermolecular interactions at the RBD-ACE2 interface, with differential distributions and the inclusion of specific H-bonds in the CoV-2 complex. Further interface analysis has shown that interfacial water promotes and stabilizes the formation of CoV-2\/hACE2 complex. This interaction causes a significant structural rigidification of the spike protein, favoring proteolytic processing of the S protein for the fusion of the viral and cellular membrane. Moreover, conformational dynamics simulations of RBD motions in SARS-CoV-2 and SARS-CoV-1 point to the role in modification of the RBD dynamics and their impact on infectivity.<\/jats:p>","DOI":"10.3390\/molecules27030799","type":"journal-article","created":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T03:33:32Z","timestamp":1643168012000},"page":"799","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Site Density Functional Theory and Structural Bioinformatics Analysis of the SARS-CoV Spike Protein and hACE2 Complex"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3001-8423","authenticated-orcid":false,"given":"Nitesh","family":"Kumawat","sequence":"first","affiliation":[{"name":"School of Mathematics, Statistics and Computational Sciences, Central University of Rajasthan, Ajmer 305817, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrejs","family":"Tucs","sequence":"additional","affiliation":[{"name":"Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-8568, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3174-7786","authenticated-orcid":false,"given":"Soumen","family":"Bera","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Tennessee, Knoxville, TN 37996, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8608-3753","authenticated-orcid":false,"given":"Gennady N.","family":"Chuev","sequence":"additional","affiliation":[{"name":"Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marat","family":"Valiev","sequence":"additional","affiliation":[{"name":"Molecular Sciences Software Group, Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99352, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2701-7294","authenticated-orcid":false,"given":"Marina V.","family":"Fedotova","sequence":"additional","affiliation":[{"name":"G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7024-0814","authenticated-orcid":false,"given":"Sergey E.","family":"Kruchinin","sequence":"additional","affiliation":[{"name":"G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Tsuda","sequence":"additional","affiliation":[{"name":"Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-8568, Japan"},{"name":"RIKEN Center for Advanced Intelligence Project, Tokyo 103-0027, Japan"},{"name":"Research and Services Division of Materials Data and Integrated System, National Institute for Materials Science, Tsukuba 305-0044, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2398-9523","authenticated-orcid":false,"given":"Adnan","family":"Sljoka","sequence":"additional","affiliation":[{"name":"RIKEN Center for Advanced Intelligence Project, Tokyo 103-0027, Japan"},{"name":"Department of Chemistry, York University, Toronto, ON M3J 1P3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Mathematics, School of Physical Sciences, Sikkim University, Gangtok 737102, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.cell.2020.09.018","article-title":"Molecular Architecture of the SARS-CoV-2 Virus","volume":"183","author":"Yao","year":"2020","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11727","DOI":"10.1073\/pnas.2003138117","article-title":"Cell entry mechanisms of SARS-CoV-2","volume":"117","author":"Shang","year":"2020","journal-title":"Proc. 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