Dysfunction of Dinitrobenzene-Bound Mitochondrial Proteins
1,3-dinitrobenzene (DNB) produces selective acute energy deprivation syndrome by targeting mitochondria of brainstem astrocytes. The molecular basis for toxicity remains elusive.
We hypothesize DNB binds widely to potential target proteins, but that selective toxicity arises from high-affinity binding to an undiscovered critical target, and/or lower-affinity binding to a set of targets likely found in mitochondria of affected astrocytes.
We will test this hypothesis in silico to identify candidate DNB-binding proteins in the mitochondrial proteome. From inverse docking of DNB to targets in the NIST human mitochondrial protein database, DNB-binding proteins will be quantified in terms of relative binding strength.
Molecular dynamics simulations will be carried out for targets with high DNB affinity to elucidate direct and indirect mechanisms of DNB on mitochondrial protein function, with particular attention to motor proteins.
The results will yield insight into selective toxicity of DNB and suggest hypotheses for future research suitable for NIH support.