Mutations in Parkinson's Disease Associated Protein DJ-1 Alter the Energetics of DJ-1 Dimerization

Journal of Chemical Information and Modeling
Abhishek KumarPriyadarshi Satpati

Abstract

Patients suffering from familial Parkinson's disease are linked to mutated DJ-1 protein. Wild-type DJ-1 occurs as a homodimer, which appears to be crucial for its function. It has been established that mutation (L166P) in DJ-1 protein could destabilize the DJ-1 homodimer. Hence, dimerization aspect of DJ-1 is fundamentally important for understanding its link to the disease. X-ray structures of wild-type DJ-1 dimer have given an atomic insight into the interaction network at the dimer interface. However, the energetics of dimerization in the wild-type and its mutant protein is unknown. Using the X-ray structure of wild-type DJ-1 as the template, we report ∼1.55 μs of molecular dynamics simulations to quantitatively estimate the relative free energy of DJ-1 dimerization in the disease linked variant (L166P, A104T, and M26I) with respect to its wild-type analogue. The results suggest that dimerization is disfavored for L166P and A104T mutations, severely for the former. Notably, the M26I mutation does not alter the energetics of DJ-1 dimerization. The dynamics of the DJ-1 dimer is significantly altered in response to the L166P and A104T mutations, resulting in the significant loss of interactions at the dimer interface. L166P mut...Continue Reading

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Citations

Jun 27, 2021·Progress in Neurobiology·Maoxin Huang, Shengdi Chen
Oct 30, 2021·Physical Chemistry Chemical Physics : PCCP·Amit Kumar, Harish Vashisth

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