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

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 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.

Conformational dynamics and energetics of viral RNA recognition by lab-evolved proteins

“…The coupling parameter values λ = 0 and 1, correspond to physical end states, whereas an intermediate value corresponds to a mixed unphysical state. Using the previously described 55 FEP method, we obtained the total free energy change Δ G along the variable horizontal paths by summing over the intermediate states as the following: , where U m = (1 − λ m ) U I + λ m U F with the coupling parameter λ m varying from 0 to 1, and the total number of intermediate points m = 1,…,( n − 1). Here, β is 1/ k B T , with k B as Boltzmann*s constant and T is the temperature.…”

“…The coupling parameter values l = 0 and 1, correspond to physical end states, whereas an intermediate value corresponds to a mixed unphysical state. Using the previously described 55 FEP method, we obtained the total free energy change DG along the variable horizontal paths by summing over the intermediate states as the following:…”

Role of Mutations in Differential Recognition of Viral RNA Molecules by Peptides

“…The coupling parameter values λ = 0 and 1 correspond to the physical end states, whereas an intermediate value corresponds to a mixed unphysical state. Using the previously described FEP method, we obtained the total free energy change along the horizontal paths by summing over the intermediate states in the following way: Δ G (I → F) = G F – G I = −β –1 ln⟨exp­[−β ( U m+1 – U m )]⟩ m , where U m = (1 – λ m ) U I + λ m U F with the coupling parameter λ m varying from 0 to 1, and the total number of intermediate points m = 1,...,( n – 1). Here, β is 1/ k B T , with k B as Boltzmann’s constant and T as the temperature.…”

“…Specifically, we report free energy changes on mutations in each peptide to provide a detailed explanation for a higher affinity of the P2 peptide over the P1 peptide for RRE RNA. To compute the free energy changes, we used the free energy perturbation (FEP) method ,, with an appropriate thermodynamic cycle (Figure S3) to quantify the relative changes in the binding affinities of peptides for RRE RNA. We also studied the dynamics of unliganded RNA molecules (R1 and R2) and the peptide-RNA complexes (P1/R1 and P2/R2) by all-atom MD simulations to further probe conformational diffferences (Table S1 and Figure S2).…”

PARK Genes Link Mitochondrial Dysfunction and Alpha-Synuclein Pathology in Sporadic Parkinson’s Disease

“…Mutations in DJ-1 were identified as a rare cause of early onset recessive PD in 2003 ( Bonifati et al, 2003 ). Around 20 pathogenic DJ-1 mutations have been identified with reduced protein due to rapid degradation ( Ramsey and Giasson, 2010 ), and less dimerization into its functional form ( Kumar et al, 2019 ). The autopsy of a patient with L172Q mutation showed severe DA neuronal loss in the substantia nigra with Lewy pathology ( Taipa et al, 2016 ).…”