{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:26:50Z","timestamp":1787315210852,"version":"build-2736575974"},"reference-count":58,"publisher":"National Academy of Sciences","issue":"45","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R35 GM122472"],"award-info":[{"award-number":["R35 GM122472"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["MCB 2142727"],"award-info":[{"award-number":["MCB 2142727"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,11,11]]},"abstract":"\n Drug resistance poses a major global health challenge, necessitating the development of effective therapeutic strategies. The main challenge is to predict drug-resistant mutations and design drugs that retain efficacy against such evolving targets. Our previous effort in computing the vitality value has provided a framework in assessing drug resistance. While promising, the approach lacked accuracy due to insufficient information about mutation tendencies and protein stability. In this study, we used the Stanford University HIV Drug Resistance Database and observed that drug resistance, usually quantified as\n \n \n \n \n K<\/mml:mi>\n \n i<\/mml:mi>\n <\/mml:mrow>\n \n mutant<\/mml:mi>\n <\/mml:mrow>\n <\/mml:msubsup>\n \/<\/mml:mo>\n \n K<\/mml:mi>\n \n i<\/mml:mi>\n <\/mml:mrow>\n \n WT<\/mml:mi>\n <\/mml:mrow>\n <\/mml:msubsup>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:inline-formula>\n , exhibits a positive correlation with the Maximum Entropy energy,\n \n \n \n E<\/mml:mi>\n \n M<\/mml:mi>\n a<\/mml:mi>\n x<\/mml:mi>\n E<\/mml:mi>\n n<\/mml:mi>\n t<\/mml:mi>\n <\/mml:mrow>\n <\/mml:msub>\n <\/mml:math>\n <\/jats:inline-formula>\n . However, both drug resistance and vitality are also correlated with the number of mutations, indicating that the virus cannot easily gain resistance through specific mutational pathways and must sacrifice stability and function to escape inhibition. To overcome this number dependence, we looked for a system with less extensive mutagenesis and chose HCV protease. In this case, resistance substitutions cluster at low\n \n \n \n E<\/mml:mi>\n \n M<\/mml:mi>\n a<\/mml:mi>\n x<\/mml:mi>\n E<\/mml:mi>\n n<\/mml:mi>\n t<\/mml:mi>\n <\/mml:mrow>\n <\/mml:msub>\n <\/mml:math>\n <\/jats:inline-formula>\n values, reflecting a limited mutational space. This restricted landscape enables\n \n \n \n E<\/mml:mi>\n \n M<\/mml:mi>\n a<\/mml:mi>\n x<\/mml:mi>\n E<\/mml:mi>\n n<\/mml:mi>\n t<\/mml:mi>\n <\/mml:mrow>\n <\/mml:msub>\n <\/mml:math>\n <\/jats:inline-formula>\n to predict evolutionary pathways of resistance and to guide the identification of robust therapeutic candidates.\n <\/jats:p>","DOI":"10.1073\/pnas.2517715122","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T17:46:47Z","timestamp":1762278407000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Exploring evolutionary trajectories of drug resistance"],"prefix":"10.1073","volume":"122","author":[{"given":"Linfeng","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoxuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arieh","family":"Warshel","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"e_1_3_4_1_2","volume-title":"Global Action Plan on Antimicrobial Resistance","author":"World Health Organization","year":"2015","unstructured":"World Health Organization, Global Action Plan on Antimicrobial Resistance (World Health Organization, 2015)."},{"key":"e_1_3_4_2_2","volume-title":"HIV Drug Resistance Report 2021","author":"World Health Organization","year":"2021","unstructured":"World Health Organization, HIV Drug Resistance Report 2021 (World Health Organization, ed. 1, 2021).","edition":"1"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1165706"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1002251"},{"key":"e_1_3_4_5_2","first-page":"559","article-title":"2022 update of the drug resistance mutations in HIV-1","volume":"30","author":"Wensing A. 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