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.
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