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Using simple molecular orbital calculations to predict disease: fast DFT methods applied to enzymes implicated in PKU, Parkinson's disease and Obsessive Compulsive Disorder

2007; American Institute of Physics; Linguagem: Inglês

10.1063/1.2793395

1935-0465

Laura R. Hofto, Meghan E. Hofto, Jessica Cross, Mauricio Cafiero, Arno Siebes, Michael R. Berthold, Robert C. Glen, Ad Feelders,

Carbohydrate Chemistry and Synthesis

Many diseases can be traced to point mutations in the DNA coding for specific enzymes. These point mutations result in the change of one amino acid residue in the enzyme. We have developed a model using simple molecular orbital calculations which can be used to quantitatively determine the change in interaction between the enzyme's active site and necessary ligands upon mutation. We have applied this model to three hydroxylase proteins: phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase, and we have obtained excellent correlation between our results and observed disease symptoms. Furthermore, we are able to use this agreement as a baseline to screen other mutations which may also cause onset of disease symptoms. Our focus is on systems where the binding is due largely to dispersion, which is much more difficult to model inexpensively than pure electrostatic interactions. Our calculations are run in parallel on a sixteen processor cluster of 64‐bit Athlon processors.