Molecular dynamics simulation of RAC1 protein and its de novo variants related to developmental disorders

Neurodevelopmental disorders (NDDs) are conceptualized as childhood disability, but it has increasingly been recognized as lifelong neurological conditions that could notably impact adult functioning and quality of life. About 1%-3% of the general population suffers from NDDs including ADHD, ASD, IDD, communication disorders, motor disorders, etc. Studies suggest that Rho GTPases are key in neuronal development, highlighting the importance of altered GTPase signaling in NDDs. RAC1, a member of the Rho GTPase family, plays a critical role in neurogenesis, migration, synapse formation, axon growth, and regulation of actin cytoskeleton dynamics. We performed 6µs all-atom molecular dynamics simulation of native RAC1 (PDB: 3TH5) and three-point mutations (C18Y, N39S, and Y64D) related to developmental disorders to understand the impact of mutations on protein stability and functional dynamics. Our analysis, which included root mean square deviation (RMSD), root mean square fluctuation (RMSF), solvent accessible surface area (SASA), radius of gyration (Rg), free energy landscape (FEL), and principal component analysis (PCA), revealed that the N39S and Y64D mutations induced significant structural changes in RAC1. These alterations primarily occurred in the functional region adjacent to switch II, a region crucial for complex conformational rearrangements during the GDP and GTP exchange cycle.Communicated by Ramaswamy H. Sarma.