Atomistic simulations reveal impacts of missense mutations on the structure and function of SynGAP1
: Ali, Aliaa E.; Li, Li-Li; Courtney, Michael J.; Pentikäinen, Olli T.; Postila, Pekka A.
Publisher: OXFORD UNIV PRESS
: OXFORD
: 2024
: Briefings in Bioinformatics
: BRIEFINGS IN BIOINFORMATICS
: BRIEF BIOINFORM
: bbae458
: 25
: 6
: 13
: 1467-5463
: 1477-4054
DOI: https://doi.org/10.1093/bib/bbae458
: https://doi.org/10.1093/bib/bbae458
: https://research.utu.fi/converis/portal/detail/Publication/458357941
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's 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.
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The authors of this manuscript have received financial support from the SynGAP Research Fund (PAP, AEA, LLL, MJC, OTP), Leon and friends e.V (MJC and LLL), the Research Council of Finland (ID 348983 to M.J.C., ID 346939 to LLL.) and Novo Nordisk Foundation (OTP; Pioneer Innovator Grant, grant number NNF21OC0068926; Distinguished Innovator Grant; grant number NNF22OC0075825) funded the research. This research was also supported by the Research Council of Finland’s Flagship InFLAMES (PAP). The funding decision numbers are 337530 and 357910.
