Structural insights into the novel Parkinson’s-linked R1501W mutation in the Roc domain of leucine-rich repeat kinase 2

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ABSTRACT Missense mutations in the Leucine-rich repeat kinase 2 (LRRK2) protein are strongly linked to the pathogenicity of both sporadic and familial Parkinson's Disease (PD). Considering their prevalence and functional consequence, mutations causing kinase dysfunction have experienced the greatest exploration. However, variants of LRRK2 with unaltered kinase activity have also been found to cause PD. This study focuses on one such case: the novel R1501W mutation in the Roc-COR (GTPase) domain of LRRK2. Given its novelty, there are scarcely any studies inspecting this variant. Thus, we employed molecular dynamics simulations of 200 ns alongside structural analyses such as root-mean-square (RMS) fluctuation, RMS deviation, radius of gyration, solvent-accessible surface-area, principal component analysis, and free energy landscape to characterise the structural changes occurring in the R1501W mutant in comparison to the wild-type. Our results reveal the introduction of a closed hydrophobic nest in the mutated region, as well as an increase in flexibility, instability, and compactness of the tertiary structure. We speculate that these alterations contribute to a kinase-independent mechanism for pathogenesis. Overall, our investigation showcases the structural dynamics of R1501W mutant LRRK2, providing a backbone for the design of future studies to further inspect the pathogenic pathway employed by this novel variant.