The Effect of N52R Mutation at the SPN-ARR Interface on the Conformational Dynamics of SHANK3

Background:: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition. The genetic basis of ASD involves numerous loci converging on neural pathways, particularly affecting excitatory synapses. SHANK3, an essential protein in the post-synaptic neurons, has been implicated in ASD, with mutations affecting its N-terminal, including the SPN domain. Objective: This study aims to investigate the impact of the N52R mutation on SHANK3 and assess the dynamics, stability, flexibility, and compactness of the N52R mutant compared to SHANK3 WT. Methods: Molecular dynamics simulations were conducted to investigate the structural dynamics of SHANK3 WT and the N52R mutant. The simulations involved heating dynamics, density equilibrium, and production dynamics. The trajectories were analyzed for RMSD, RMSF, Rg, hydrogen bond analysis, and secondary structure. Results: The simulations revealed that the N52R mutant disrupts the stability and folding of SHANK3, affecting intramolecular contacts between SPN and ARR. This disruption opens up the distance between SPN and ARR domains, potentially influencing the protein's interactions with partners, including αCaMKII and α-Fodrin. The altered conformation of the SPN-ARR tandem in the N52R mutant suggests a potential impact on dendritic spine shape and synaptic plasticity. Conclusion: The findings shed light on the structural consequences of the N52R mutation in SHANK3, emphasizing its role in influencing intramolecular interactions and potential effects on synaptic function. Understanding these molecular dynamics contributes to unraveling the intricate relationship between genetic variations in SHANK3 and clinical traits associated with ASD. Further investigations are warranted to explore the physiological implications of these structural alterations in vivo.