{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T01:56:52Z","timestamp":1776304612309,"version":"3.50.1"},"reference-count":133,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T00:00:00Z","timestamp":1727049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SynGAP Research"},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF21OC0068926"],"award-info":[{"award-number":["NNF21OC0068926"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF22OC0075825"],"award-info":[{"award-number":["NNF22OC0075825"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research Council of Finland\u2019s Flagship InFLAMES","award":["337530"],"award-info":[{"award-number":["337530"]}]},{"name":"Research Council of Finland\u2019s Flagship InFLAMES","award":["357910"],"award-info":[{"award-number":["357910"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>De novo mutations in the synaptic GTPase activating protein (SynGAP) are associated with neurological disorders like intellectual disability, epilepsy, and autism. SynGAP is also implicated in Alzheimer\u2019s disease and cancer. Although pathogenic variants are highly penetrant in neurodevelopmental conditions, a substantial number of them are caused by missense mutations that are difficult to diagnose. Hence, in silico mutagenesis was performed for probing the missense effects within the N-terminal region of SynGAP structure. Through extensive molecular dynamics simulations, encompassing three 150-ns replicates for 211 variants, the impact of missense mutations on the protein fold was assessed. The effect of the mutations on the folding stability was also quantitatively assessed using free energy calculations. The mutations were categorized as potentially pathogenic or benign based on their structural impacts. Finally, the study introduces wild-type-SynGAP in complex with RasGTPase at the inner membrane, while considering the potential effects of mutations on these key interactions. This study provides structural perspective to the clinical assessment of SynGAP missense variants and lays the foundation for future structure-based drug discovery.<\/jats:p>","DOI":"10.1093\/bib\/bbae458","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T13:26:34Z","timestamp":1727097994000},"source":"Crossref","is-referenced-by-count":3,"title":["Atomistic simulations reveal impacts of missense mutations on the structure and function of SynGAP1"],"prefix":"10.1093","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2503-6854","authenticated-orcid":false,"given":"Aliaa E","family":"Ali","sequence":"first","affiliation":[{"name":"MedChem.fi, Institute of Biomedicine, Integrative Physiology and Pharmacology, University of Turku , FI-20014 Turku,","place":["Finland"]},{"name":"InFLAMES Research Flagship, University of Turku , 20014 Turku,","place":["Finland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Li","family":"Li","sequence":"additional","affiliation":[{"name":"Neuronal Signalling Laboratory and Turku Screening Unit , Turku Bioscience Centre, , Turku,","place":["Finland"]},{"name":"University of Turku and \u00c5bo Akademi University , Turku Bioscience Centre, , Turku,","place":["Finland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J","family":"Courtney","sequence":"additional","affiliation":[{"name":"Neuronal Signalling Laboratory and Turku Screening Unit , Turku Bioscience Centre, , Turku,","place":["Finland"]},{"name":"University of Turku and \u00c5bo Akademi University , Turku Bioscience Centre, , Turku,","place":["Finland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olli T","family":"Pentik\u00e4inen","sequence":"additional","affiliation":[{"name":"MedChem.fi, Institute of Biomedicine, Integrative Physiology and Pharmacology, 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