{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:53:32Z","timestamp":1786978412573,"version":"build-2736575974"},"reference-count":62,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Phenylketonuria (PKU) is a genetic disorder that if left untreated can lead to behavioral problems, epilepsy, and even mental retardation. PKU results from mutations within the phenylalanine\u20104\u2010hydroxylase (PAH) gene that encodes for the PAH protein. The study of all PAH causing mutations is improbable using experimental techniques. In this study, a collection of in silico resources, sorting intolerant from tolerant, Polyphen\u20102, PhD\u2010SNP, and MutPred were used to identify possible pathogenetic and deleterious PAH non\u2010synonymous single nucleotide polymorphisms (nsSNPs). We identified two variants of PAH, I65N and L311P, to be the most deleterious and disease causing nsSNPs. Molecular dynamics (MD) simulations were carried out to characterize these point mutations on the atomic level. MD simulations revealed increased flexibility and a decrease in the hydrogen bond network for both mutants compared to the native protein. Free energy calculations using the MM\/GBSA approach found that BH\n                    <jats:sub>4<\/jats:sub>\n                    , a drug\u2010based therapy for PKU patients, had a higher binding affinity for I65N and L311P mutants compared to the wildtype protein. We also identify important residues in the BH\n                    <jats:sub>4<\/jats:sub>\n                    binding pocket that may be of interest for the rational drug design of other PAH drug\u2010based therapies. Lastly, free energy calculations also determined that the I65N mutation may impair the dimerization of the N\u2010terminal regulatory domain of PAH.\n                  <\/jats:p>","DOI":"10.1002\/prot.26051","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T03:34:46Z","timestamp":1611545686000},"page":"683-696","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["<scp>In silico<\/scp>\n                    screening and molecular dynamics simulation of deleterious\n                    <scp>PAH<\/scp>\n                    mutations responsible for phenylketonuria genetic disorder"],"prefix":"10.1002","volume":"89","author":[{"given":"Andrea","family":"Lopez","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Illinois at Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Havranek","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Illinois at Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George A.","family":"Papadantonakis","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Illinois at Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5769-6844","authenticated-orcid":false,"given":"Shahidul M.","family":"Islam","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Illinois at Chicago  Chicago Illinois 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