Exploring the Impact of LRRK2 WD40 G2294R Mutation on Conformation and Dimerisation Dynamics: Insights From Molecular...

LRRK2 has gained prominence in treating Parkinson's disease as a potential drug target. Mutations in the WD40 domain, like G2294R, are notable for their influence on the stability and dimerisation of the LRRK2. Studies have shown that G2294R could result in the WD40 distortion and destabilised LRRK2 protein. However, the underlying mechanism remains unclear. To elucidate how the G2294R mutation in the WD40 domain affects the structural and functional conformation of LRRK2, the structure of WD40 G2294R was constructed using homology modelling, and the molecular dynamics simulations on G2294R and wild-type dimers and monomers were carried out. The results show that distortion mainly occurs in the areas of β3, L1, β5, L2, and β7. The dimerisation was enhanced through the conformational changes in the G2294R variant, while the domains show different contributions towards the dimerisation. Our study reveals the effects of G2294R on the WD40. It explores its role in dimerisation and distortion, which could contribute to developing novel WD40 inhibitors and elucidate the molecular mechanism of WD40 dimerisation-monomerisation equilibrium.