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

Missense variants in 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 (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 variants on protein function that underlies neurodevelopment and human disorders.