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Models reported previously have had two major problems: lack of information on the 3D protein structure and processing of incomplete sequencing data in the modeling procedure. We propose obtaining the 3D structural information of viral proteins by using homology modeling and molecular field mapping, instead of just their primary amino acid sequences. The molecular field potential parameters reflect the physicochemical characteristics associated with the 3D structure of the proteins. We also introduce the Bayesian conditional mutual information theory to estimate the probabilities of occurrence of all possible protein candidates from an incomplete sequencing sample. This approach allows for the effective use of uncertain information for the modeling process. We applied these data analysis techniques to the HIV-1 protease inhibitor dataset and developed drug resistance prediction models with reasonable performance.<\/jats:p>","DOI":"10.1371\/journal.pone.0255693","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T13:29:38Z","timestamp":1628083778000},"page":"e0255693","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Prediction of HIV drug resistance based on the 3D protein structure: Proposal of molecular field mapping"],"prefix":"10.1371","volume":"16","author":[{"given":"Ryosaku","family":"Ota","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"So","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Tsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuriko","family":"Higuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiyoshi","family":"Yamashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,8,4]]},"reference":[{"issue":"6","key":"pone.0255693.ref001","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.coviro.2011.10.020","article-title":"Drug resistance in HIV-1","volume":"1","author":"DR Kuritzkes","year":"2011","journal-title":"Curr Opin Virol"},{"issue":"2","key":"pone.0255693.ref002","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1093\/cid\/ciy463","article-title":"Human Immunodeficiency Virus Drug Resistance: 2018 Recommendations of the International Antiviral Society\u2013USA Panel","volume":"68","author":"HF G\u00fcnthard","year":"2019","journal-title":"Clin Infect Dis"},{"issue":"5","key":"pone.0255693.ref003","doi-asserted-by":"crossref","first-page":"560","DOI":"10.3390\/v12050560","article-title":"Drug Resistance Prediction Using Deep Learning Techniques on HIV-1 Sequence Data","volume":"12","author":"MC Steiner","year":"2020","journal-title":"Viruses"},{"issue":"13","key":"pone.0255693.ref004","doi-asserted-by":"crossref","first-page":"3850","DOI":"10.1093\/nar\/gkg575","article-title":"Geno2pheno: estimating phenotypic drug resistance from HIV-1 genotypes","volume":"31","author":"N Beerenwinkel","year":"2003","journal-title":"Nucleic Acids Res"},{"issue":"11","key":"pone.0255693.ref005","doi-asserted-by":"crossref","first-page":"2751","DOI":"10.3390\/molecules23112751","article-title":"A Computational Approach for the Prediction of HIV Resistance Based on Amino Acid and Nucleotide Descriptors","volume":"23","author":"O Tarasova","year":"2018","journal-title":"Molecules"},{"issue":"Suppl 5","key":"pone.0255693.ref006","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1186\/1471-2164-15-S5-S1","article-title":"Prediction of HIV drug resistance from genotype with encoded three-dimensional protein structure","volume":"15","author":"X Yu","year":"2014","journal-title":"Bmc Genomics"},{"issue":"Suppl 8","key":"pone.0255693.ref007","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1186\/s12859-016-1114-6","article-title":"Automated prediction of HIV drug resistance from genotype data","volume":"17","author":"C Shen","year":"2016","journal-title":"Bmc Bioinformatics"},{"issue":"1","key":"pone.0255693.ref008","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1093\/nar\/gkg100","article-title":"Human immunodeficiency virus reverse transcriptase and protease sequence database","volume":"31","author":"S-Y Rhee","year":"2003","journal-title":"Nucleic Acids Res"},{"key":"pone.0255693.ref009","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.compbiolchem.2014.10.001","article-title":"Silva MB e, Buriol LS, Lamb LC. 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I. 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