The local, GGA, meta-GGA, hybrid, and double-hybrid dispersion functionals were used to evaluate the structure and interaction energies of novel ligands in the TyrOH active site. TyrOH is the rate determining enzyme in the catecholamine-dopamine pathway, converting tyrosine to L-DOPA. The inhibition of TyrOH, however, reduces dopamine in the brain to undetectable levels (Spector et al., 1965). A crystal structure of the active site of tyrosine hydroxylase with a known inhibitor bound was obtained from the protein data bank (PDB ID: 2TOH) (Goodwill et al., 1998). In this work, dopaminergic derivatives, which could be potential treatments for Parkinson’s disease, were inserted into the enzymatic active site in silico in order to test the strength of the interactions between the ligand and active site, to determine if any of these derivatives could be effective inhibitors. Various local, GGA, meta-GGA, hybrid, and double-hybrid dispersion functionals were used to optimize structures and to analyze interaction energies. The novel dopaminergic derivatives were optimized in the active site with implicit solvent with all of the above functional types and 6- 31G with relaxed amino acid side chains. Counterpoise-corrected interaction energies between the ligands and protein were determined using the same DFT methods mentioned above with the 6-311+G* basis set. This work shows significant differences between the methods within the same complex. The analysis has also helped to determine promising ligands for the treatment of Parkinson’s disease that would not inhibit TyrOH.<br/>

Survey of quantum chemical methods for computing interaction energies in organometallic systems

2019 Spring National Meeting

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