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At the protein level, empirical substitution models are traditionally used due to their simplicity, but they ignore the variability of substitution patterns among protein sites. Next, in order to improve the realism of the modeling of protein evolution, a series of structurally constrained substitution models were presented, but still they usually ignore constraints on the protein activity. Here, we present a substitution model of protein evolution with selection on both protein structure and enzymatic activity, and that can be applied to phylogenetics. In particular, the model considers the binding affinity of the enzyme\u2013substrate complex as well as structural constraints that include the flexibility of structural flaps, hydrogen bonds, amino acids backbone radius of gyration, and solvent-accessible surface area that are quantified through molecular dynamics simulations. We applied the model to the HIV-1 protease and evaluated it by phylogenetic likelihood in comparison with the best-fitting empirical substitution model and a structurally constrained substitution model that ignores the enzymatic activity. We found that accounting for selection on the protein activity improves the fitting of the modeled functional regions with the real observations, especially in data with high molecular identity, which recommends considering constraints on the protein activity in the development of substitution models of evolution.<\/jats:p>","DOI":"10.1093\/molbev\/msae026","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T11:10:56Z","timestamp":1707131456000},"source":"Crossref","is-referenced-by-count":8,"title":["Substitution Models of Protein Evolution with Selection on Enzymatic Activity"],"prefix":"10.1093","volume":"41","author":[{"given":"David","family":"Ferreiro","sequence":"first","affiliation":[{"name":"CINBIO, Universidade de Vigo , 36310 Vigo , Spain"},{"name":"Department of Biochemistry, Genetics and Immunology, Universidade de Vigo , 36310 Vigo , Spain"}]},{"given":"Ruqaiya","family":"Khalil","sequence":"additional","affiliation":[{"name":"CINBIO, Universidade de Vigo , 36310 Vigo , Spain"},{"name":"Department of Biochemistry, Genetics and Immunology, Universidade de Vigo , 36310 Vigo , Spain"}]},{"given":"Sergio F","family":"Sousa","sequence":"additional","affiliation":[{"name":"UCIBIO\/REQUIMTE, BioSIM, Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto , 4200-319 Porto , Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0516-2717","authenticated-orcid":false,"given":"Miguel","family":"Arenas","sequence":"additional","affiliation":[{"name":"CINBIO, Universidade de Vigo , 36310 Vigo , Spain"},{"name":"Department of Biochemistry, Genetics and Immunology, Universidade de Vigo , 36310 Vigo , Spain"}]}],"member":"286","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"issue":"2","key":"2024021704365149400_msae026-B1","doi-asserted-by":"crossref","first-page":"e0118684","DOI":"10.1371\/journal.pone.0118684","article-title":"How structural and physicochemical determinants shape sequence constraints in a functional enzyme","volume":"10","author":"Abriata","year":"2015","journal-title":"PLoS One"},{"key":"2024021704365149400_msae026-B2","doi-asserted-by":"crossref","first-page":"319","DOI":"10.3389\/fgene.2015.00319","article-title":"Trends in substitution models of molecular evolution","volume":"6","author":"Arenas","year":"2015","journal-title":"Front Genet"},{"key":"2024021704365149400_msae026-B3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2015\/395826","article-title":"Genetic consequences of antiviral therapy on HIV-1","volume":"2015","author":"Arenas","year":"2015","journal-title":"Comput Math Methods Med"},{"key":"2024021704365149400_msae026-B4","first-page":"283","volume-title":"Environmental microbial evolution. 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