Cheminformatic quantum mechanical enzyme model design: A catechol-O-methyltransferase case study

To accurately simulate the inner workings of an enzyme active site with quantum mechanics (QM), not only must the reactive species be included in the model but also important surrounding residues, solvent, or coenzymes involved in crafting the microenvironment. Our lab has been developing the Residue Interaction Network Residue Selector (RINRUS) toolkit to utilize interatomic contact network information for automated, rational residue selection and QM-cluster model generation. Starting from an x-ray crystal structure of catechol-O-methyltransferase, RINRUS was used to construct a series of QM-cluster models. The reactant, product, and transition state of the methyl transfer reaction were computed for a total of 550 models, and the resulting free energies of activation and reaction were used to evaluate model convergence. RINRUS-designed models with only 200-300 atoms are shown to converge. RINRUS will serve as a cornerstone for improved and automated cheminformatics-based enzyme model design.

Automated summary

The lab has developed the RINRUS toolkit to simulate enzyme active sites with interatomic contact network information for rational residue selection and QM-cluster model generation. By computing methyl transfer reactions for 550 models, it was found that even smaller RINRUS-designed models can converge efficiently. RINRUS will be essential for enhancing and automating enzyme model design based on cheminformatics.