Molecular dynamics studies reveal the structural impacts of LRRK2 R1441C and LRRK2 D1994A mutations in Parkinson's disease

Abstract

Parkinson's Disease (PD) is a continuingly deteriorating neurological ailment affecting over 8.5 million patients globally as of 2019, and the numbers are expected to keep rising. To aid in identifying therapeutic targets, molecular dynamics simulations are convenient and cost-effective methods for enriching our knowledge of the molecular pathophysiology of diseases. Many proteins and their corresponding mutations have been identified to contribute to this disease, of which Leucine-rich repeat kinase 2 (LRRK2) is accountable for a significant percentage. Several mutations involving the domains in LRRK2 have been studied, which are known to interfere with various enzymatic processes, ultimately leading to trademark features of PD like aggregation of protein inclusions called Lewy Bodies (LBs), mitochondrial dysfunctions, etc. The precise molecular mechanism of the mutations' pathophysiology is still unclear. This research article looks at the structural effects of mutations, namely the R1441C and D1994A mutations, on the surrounding residues in the protein, offering novel insights into pathophysiological changes at an atomistic level. Our results indicate a gain of electrostatic interactions with a stable αβ motif within the LRR-Roc linker, amongst other changes. This article also highlights the potential involvement and importance of the αβ motif in LRRK2 associated PD.