{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:14:35Z","timestamp":1772118875126,"version":"3.50.1"},"reference-count":39,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T00:00:00Z","timestamp":1740960000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001409","name":"Department of Science and Technology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001409","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    In recent years, Human Immunodeficiency Virus (HIV) remains a significant global health challenge, with millions affected worldwide, particularly in Africa and sub\u2010Saharan regions. Despite advances in antiretroviral therapies, the genetic variability of HIV, including different subtypes and drug\u2010resistant strains, poses persistent obstacles in the development of universally effective treatments. This study focuses on the dynamics of HIV protease, a key enzyme in viral replication and maturation, particularly targeting subtype C and its double insertion (HL) variant L38HL, in the context of interaction with Darunavir (DRV), a second\u2010generation nonpeptidic protease inhibitor approved by the FDA in 2006. Through molecular dynamics simulations, structural analyses, dynamic cross\u2010correlation analyses, and binding energy calculations, we investigated differences in the binding of DRV to WT and L38HL HIV\u20101 protease. The findings highlight that the double insertion at the hinge induces variation in\n                    <jats:italic>\u03a6<\/jats:italic>\n                    and\n                    <jats:italic>\u03a8<\/jats:italic>\n                    angles, leading to increased residue fluctuations, solvent\u2010accessible surface area (SASA), and radius of gyration (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sub>g<\/jats:sub>\n                    ). This alters the overall structural compactness and the hydrophobic core crucial for drug binding. Subtle structural changes result in the loss of hydrogen bond interactions, reducing the binding energy of L38HL HIV\u20101 protease subtype C bound to DRV, leading to drug resistance.\n                  <\/jats:p>","DOI":"10.1002\/prot.26817","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T18:57:05Z","timestamp":1741719425000},"page":"1426-1435","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Structural Implications of\n                    <scp>HIV<\/scp>\n                    \u20101 Protease Subtype C Bound to Darunavir: A Molecular Dynamics Study"],"prefix":"10.1002","volume":"93","author":[{"given":"Sankaran","family":"Venkatachalam","sequence":"first","affiliation":[{"name":"Department of Biotechnology Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras  Chennai India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sowmya Ramaswamy","family":"Krishnan","sequence":"additional","affiliation":[{"name":"Department of Biotechnology Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras  Chennai India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramesh","family":"Pandian","sequence":"additional","affiliation":[{"name":"Protein Structure\u2010Function Research Unit School of Molecular and Cell Biology, University of the Witwatersrand  Johannesburg South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasien","family":"Sayed","sequence":"additional","affiliation":[{"name":"Protein Structure\u2010Function Research Unit School of Molecular and Cell Biology, University of the Witwatersrand  Johannesburg South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1776-4096","authenticated-orcid":false,"given":"M. Michael","family":"Gromiha","sequence":"additional","affiliation":[{"name":"Department of Biotechnology Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras  Chennai India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.6189183"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.6601823"},{"key":"e_1_2_9_4_1","volume-title":"HIV\/AIDS Fact Sheet","author":"World Health Organization","year":"2022"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1200-9"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/v13050839"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00872-07"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2016.08.031"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1089\/aid.2013.0153"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2012.06.015"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1086\/590943"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1159\/000331995"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/337615a0"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-411636-8.00008-0"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01697"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2009.10.003"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2012.736774"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1089\/aid.2019.0012"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00726-08"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1089\/088922299311727"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2007.09.010"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.927373"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpbi.3"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20945"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b00255"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20035"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.3c01153"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.464397"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9991(77)90098-5"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.8b00462"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar000033j"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0282(2000)56:4<275::AID-BIP10024>3.0.CO;2-E"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/ma50003a019"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.2142\/biophysico.bppb-v21.0007"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmgm.2021.107931"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja2095766"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes14020533"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9CP06657H"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep10517"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.crstbi.2024.100132"}],"container-title":["Proteins: Structure, Function, and Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prot.26817","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T07:15:59Z","timestamp":1754032559000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/prot.26817"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,3]]},"references-count":39,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1002\/prot.26817"],"URL":"https:\/\/doi.org\/10.1002\/prot.26817","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/PROT.26817\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/PROT.26817\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/PROT.26817\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/PROT.26817\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/PROT.26817\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/PROT.26817\/v1\/review1","asserted-by":"object"}]},"ISSN":["0887-3585","1097-0134"],"issn-type":[{"value":"0887-3585","type":"print"},{"value":"1097-0134","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,3]]},"assertion":[{"value":"2024-09-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}