Impact of E71S Mutation on SHANK3 Conformational Dynamics at the SPN-ARR Interface

Autism spectrum disorder (ASD) is a complicated neurological condition. The genetic factors implicated in ASD have included a variety of loci that converge on neurological pathways, mainly excitatory synapses. SHANK3, a crucial protein in post-synaptic neuron cells, has been linked to ASD through mutations in the N-terminal, substantially the SPN domain. Our study aims to evaluate the influence of the E71S mutation on SHANK3, assessing its dynamics, stability, flexibility, and compactness compared to the SHANK3 WT. We employed molecular dynamics simulations to investigate the structural dynamics of both SHANK3 WT and the E71S mutant. Simulation steps encompassed heating dynamics, density equilibration, and production, followed by trajectory analysis, including RMSD, RMSF, Rg, B-factor, hydrogen bond interactions, and changes in secondary structure. The simulations unveiled that the E71S mutation perturbs the stability and folding of SHANK3, leading to the disturbance of intramolecular contacts between the SPN and ARR domains, consequently influencing the binding with αCaMKII and α-Fodrin to its sites on the SHANK3. These findings highlight the possible role of an open-up mutation between SPN-ARR tandem on dendritic spine shape and plasticity of synaptic neurons in neurodevelopmental disorders.