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

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 mutant showed the structural difference and increased flexibility in α6, α7, α8 regions with respect to the WT. A structural difference in the α6 region was noticeable between WT and A104T mutant of DJ-1. The interaction network in the dimer interface is identical for the wild-type protein and the M26I mutant. No significant change in secondary structural content was observed for DJ-1 mutants (L166P, A104T, M26I) with respect to its WT analogue.