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.