{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:14:01Z","timestamp":1788459241484,"version":"build-2803163510"},"reference-count":81,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Tuberous sclerosis complex (TSC) is an autosomal dominant disorder resulting from the mutations in the\n                    <jats:italic>TSC1<\/jats:italic>\n                    and\n                    <jats:italic>TSC2<\/jats:italic>\n                    genes and is distinguished by benign hamartoma formation in multiple organs. The\n                    <jats:italic>TSC1<\/jats:italic>\n                    \u2013\n                    <jats:italic>TSC2<\/jats:italic>\n                    complex regulates mTORC1 signaling in response to cellular growth conditions. This study aims to predict the structural stability and functional effects of non-synonymous single-nucleotide polymorphisms (nsSNPs) in human\n                    <jats:italic>TSC1<\/jats:italic>\n                    and\n                    <jats:italic>TSC2<\/jats:italic>\n                    using computational approaches. Twelve computational tools were assessed using receiver operating characteristic (ROC) analysis and applied to identify deleterious nsSNPs. Protein stability was predicted using I-Mutant 2.0 and MUpro, while evolutionary conservation was analyzed with ConSurf. NetPhos 3.1 identified potential PTM sites, and MutPred2.0 evaluated their functional impact. Project HOPE assessed mutation-induced physicochemical changes. Structural models were validated using multiple tools, visualized in ChimeraX 1.9, and further evaluated by molecular dynamics simulation to confirm wild-type and mutant stability. A combined in silico analysis identified twelve high-risk nsSNPs in\n                    <jats:italic>TSC1<\/jats:italic>\n                    and sixteen in\n                    <jats:italic>TSC2<\/jats:italic>\n                    , all reducing protein stability, located in conserved regions, and potentially disrupting phosphorylation sites. MutPred and Project HOPE confirmed their impact on protein function. Functional analysis showed\n                    <jats:italic>TSC1<\/jats:italic>\n                    and\n                    <jats:italic>TSC2<\/jats:italic>\n                    affect mTORC1 and PI3K\u2013Akt pathways. RMSF and RMSD analyses revealed that\n                    <jats:italic>TSC1<\/jats:italic>\n                    variants rs1846545280 (G236E), and rs2132135678 (V234E), and\n                    <jats:italic>TSC2<\/jats:italic>\n                    variants rs45517223 (S758C), rs2151354925 (T836P), and rs45517365 (R1570W) had the largest structural fluctuations. Substitution with glutamic acid, a negatively charged and bulkier residue, may disrupt local folding of\n                    <jats:italic>TSC1<\/jats:italic>\n                    . Similarly, replacement of arginine with tyrosine at position 1570 may impair Rheb binding at the GAP domain of\n                    <jats:italic>TSC2<\/jats:italic>\n                    . These findings highlight potentially pathogenic nsSNPs in\n                    <jats:italic>TSC1<\/jats:italic>\n                    and\n                    <jats:italic>TSC2<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0343189","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:24:52Z","timestamp":1788456292000},"page":"e0343189","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive analysis of non-synonymous single-nucleotide polymorphism of human TSC1 and TSC2 genes: An in silico approach"],"prefix":"10.1371","volume":"21","author":[{"given":"Tasnim","family":"Alam","sequence":"first","affiliation":[{"name":"Shahjalal University of Science and Technology","place":["Sylhet, Bangladesh"],"department":["Department of Biochemistry and Molecular Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8083-4399","authenticated-orcid":true,"given":"Shangida","family":"Akther","sequence":"additional","affiliation":[{"name":"Shahjalal University of Science and Technology","place":["Sylhet, Bangladesh"],"department":["Department of Biochemistry and Molecular Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"issue":"5327","key":"pone.0343189.ref001","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1126\/science.277.5327.805","article-title":"Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34","volume":"277","author":"M van Slegtenhorst","year":"1997","journal-title":"Science"},{"issue":"13","key":"pone.0343189.ref002","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1093\/hmg\/ddn098","article-title":"Bladder tumour-derived somatic TSC1 missense mutations 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