Studying Disease-Associated UBE3A Missense Variants Using Enhanced Sampling Molecular Simulations

Mark Agostino; Fiona McKenzie; Chloe Buck; Karen J Woodward; Vanessa J Atkinson; Dimitar N Azmanov; Julian Ik-Tsen Heng

doi:10.1021/acsomega.2c00959

Studying Disease-Associated UBE3A Missense Variants Using Enhanced Sampling Molecular Simulations

ACS Omega. 2022 Jul 11;7(29):25039-25045. doi: 10.1021/acsomega.2c00959. eCollection 2022 Jul 26.

Authors

Mark Agostino^{1

2}, Fiona McKenzie^{3

4}, Chloe Buck⁵, Karen J Woodward^{6

7}, Vanessa J Atkinson⁶, Dimitar N Azmanov⁶, Julian Ik-Tsen Heng^{1

8}

Affiliations

¹ Curtin Health Innovation Research Institute, Curtin University, Kent Street, Bentley, Perth, Western Australia 6102, Australia.
² Curtin Institute for Computation, Curtin University, Kent Street, Bentley, Perth, Western Australia 6102, Australia.
³ Genetic Services of Western Australia, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, Perth, Western Australia 6008, Australia.
⁴ School of Paediatrics and Child Health, University of Western Australia, 35 Stirling Highway, Crawley, Perth, Western Australia 6009, Australia.
⁵ School of Allergy and Clinical Immunology, University of Cape Town, Cape Town 7925, South Africa.
⁶ Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre E Block, Perth, Western Australia 6009, Australia.
⁷ School of Biomedical Sciences, University of Western Australia, 35 Stirling Highway, Crawley, Perth, Western Australia 6009, Australia.
⁸ Curtin Medical School, Curtin University, Kent Street, Bentley, Perth, Western Australia 6102, Australia.

Abstract

Missense variants in UBE3A underlie neurodevelopmental conditions such as Angelman Syndrome and Autism Spectrum Disorder, but the underlying molecular pathological consequences on protein folding and function are poorly understood. Here, we report a novel, maternally inherited, likely pathogenic missense variant in UBE3A (NM_000462.4(UBE3A_v001):(c.1841T>C) (p.(Leu614Pro))) in a child that presented with myoclonic epilepsy from 14 months, subsequent developmental regression from 16 months, and additional features consistent with Angelman Syndrome. To understand the impact of p.(Leu614Pro) on UBE3A, we used adiabatic biased molecular dynamics and metadynamics simulations to investigate conformational differences from wildtype proteins. Our results suggest that Leu614Pro substitution leads to less efficient binding and substrate processing compared to wildtype. Our results support the use of enhanced sampling molecular simulations to investigate the impact of missense UBE3A variants on protein function that underlies neurodevelopment and human disorders.