{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T12:31:40Z","timestamp":1769085100023,"version":"3.49.0"},"reference-count":63,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T00:00:00Z","timestamp":1695340800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Macau Science and Technology Development Fund","award":["085\/2017\/A2"],"award-info":[{"award-number":["085\/2017\/A2"]}]},{"name":"Macau Science and Technology Development Fund","award":["0077\/2019\/AMJ"],"award-info":[{"award-number":["0077\/2019\/AMJ"]}]},{"name":"Macau Science and Technology Development Fund","award":["0032\/2022\/A1"],"award-info":[{"award-number":["0032\/2022\/A1"]}]},{"DOI":"10.13039\/501100004733","name":"University of Macau","doi-asserted-by":"publisher","award":["SRG2017-00097-FHS"],"award-info":[{"award-number":["SRG2017-00097-FHS"]}],"id":[{"id":"10.13039\/501100004733","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004733","name":"University of Macau","doi-asserted-by":"publisher","award":["MYRG2019-00018-FHS"],"award-info":[{"award-number":["MYRG2019-00018-FHS"]}],"id":[{"id":"10.13039\/501100004733","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004733","name":"University of Macau","doi-asserted-by":"publisher","award":["MYRG2020-00094-FHS"],"award-info":[{"award-number":["MYRG2020-00094-FHS"]}],"id":[{"id":"10.13039\/501100004733","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100022657","name":"Faculty of Health Sciences, University of Macau","doi-asserted-by":"publisher","award":["FHSIG\/SW\/0007\/2020P"],"award-info":[{"award-number":["FHSIG\/SW\/0007\/2020P"]}],"id":[{"id":"10.13039\/501100022657","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u00a0<\/jats:title>\n                  <jats:p>Phosphatase and tensin homolog (PTEN), a tumor suppressor with dual phosphatase properties, is a key factor in PI3K\/AKT signaling pathway. Pathogenic germline variation in PTEN can abrogate its ability to dephosphorylate, causing high cancer risk. Lack of functional evidence lets numerous PTEN variants be classified as variants of uncertain significance (VUS). Utilizing Molecular Dynamics (MD) simulations, we performed a thorough evaluation for 147 PTEN missense VUS, sorting them into 66 deleterious and 81 tolerated variants. Utilizing replica exchange molecular dynamic (REMD) simulations, we further assessed the variants situated in the catalytic core of PTEN\u2019s phosphatase domain and uncovered conformational alterations influencing the structural stability of the phosphatase domain. There was a high degree of agreement between our results and the variants classified by Variant Abundance by Massively Parallel Sequencing, saturation mutagenesis, multiplexed functional data and experimental assays. Our extensive analysis of PTEN missense VUS should benefit their clinical applications in PTEN-related cancer.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Significance statement<\/jats:title>\n                  <jats:p>Classification of PTEN variants affecting its lipid phosphatase activity is important for understanding the roles of PTEN variation in the pathogenesis of hereditary and sporadic malignancies. Of the 3000 variants identified in PTEN, 1296 (43%) were assigned as VUS. Here, we applied MD and REMD simulations to investigate the effects of PTEN missense VUS on the structural integrity of the PTEN phosphatase domain consisting the WPD, P and TI active sites. We classified a total of 147 missense VUS into 66 deleterious and 81 tolerated variants by referring to the control group comprising 54 pathogenic and 12 benign variants. The classification was largely in concordance with these classified by experimental approaches.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bib\/bbad361","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T15:40:08Z","timestamp":1697470808000},"source":"Crossref","is-referenced-by-count":5,"title":["Classification of PTEN missense VUS through exascale simulations"],"prefix":"10.1093","volume":"24","author":[{"given":"Siddharth","family":"Sinha","sequence":"first","affiliation":[{"name":"Ministry of Education Frontiers Science Center for Precision Oncology , Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, , Macau S.A.R , China"},{"name":"University of Macau , Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, , Macau S.A.R , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaheng","family":"Li","sequence":"additional","affiliation":[{"name":"Ministry of Education Frontiers Science Center for Precision Oncology , Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, , Macau S.A.R , China"},{"name":"University of Macau , Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, , Macau S.A.R , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Tam","sequence":"additional","affiliation":[{"name":"Ministry of Education Frontiers Science Center for Precision Oncology , Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, , Macau S.A.R , China"},{"name":"University of Macau , Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, , Macau S.A.R , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"San Ming","family":"Wang","sequence":"additional","affiliation":[{"name":"Ministry of Education Frontiers Science Center for Precision Oncology , Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, , Macau S.A.R , China"},{"name":"University of Macau , Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, , Macau S.A.R , China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,10,14]]},"reference":[{"key":"2023101612122528100_ref1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1677\/erc.0.0070115","article-title":"PTEN, a unique tumor suppressor gene","volume":"7","author":"Dahia","year":"2000","journal-title":"Endocr Relat Cancer"},{"key":"2023101612122528100_ref2","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1126\/science.275.5308.1943","article-title":"PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate 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