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Natural polymorphisms (NPs) contained within several African and Brazilian protease (PR) variants have been shown to induce a conformational landscape of more closed conformations compared to the sequence of subtype B prevalent in North America and Western Europe. Here we demonstrate through experimental pulsed EPR distance measurements and molecular dynamic (MD) simulations that the two common NPs D60E and I62V found within subtypes F and H can induce a closed conformation when introduced into HIV-1PR subtype B. Specifically, D60E alters the conformation in subtype B through the formation of a salt bridge with residue K43 contained within the nexus between the flap and hinge region of the HIV-1 PR fold. On the other hand, I62V modulates the packing of the hydrophobic cluster of the cantilever and fulcrum, also resulting in a more closed conformation.<\/jats:p>","DOI":"10.3390\/v16020236","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T09:24:08Z","timestamp":1706865848000},"page":"236","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Natural Polymorphisms D60E and I62V Stabilize a Closed Conformation in HIV-1 Protease in the Absence of an Inhibitor or Substrate"],"prefix":"10.3390","volume":"16","author":[{"given":"Trang T.","family":"Tran","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Florida, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail E.","family":"Fanucci","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Florida, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,2]]},"reference":[{"key":"ref_1","first-page":"111","article-title":"2019 update of the drug resistance mutations in HIV-1","volume":"27","author":"Wensing","year":"2019","journal-title":"Top. 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