The rate of progress in developing new pharmaceuticals could be accelerated if experimental researchers had practical methods for modeling enzyme mechanisms. Unfortunately, all current programs have severe limitations, either being too slow, too complicated, or too inaccurate. Although an efficient and accurate method for modeling mechanisms in enzyme-catalyzed reactions has been developed and made available in the form of the stand-alone program MOPAC2012, very few users of this program have used it for that purpose. Instead, most users have used it for modeling simpler systems, such as the docking of substrates into active sites in enzymes. This reluctance by experimentalists to model enzyme mechanisms can be attributed to the severe learning-curve barrier currently necessary before useful results can be obtained. Experimentalists want to focus on the chemistry involved, and, as far as possible, do not want to become involved in computational details, software requirements, restrictions, etc. As a result, tools that can be used efficiently by computational chemists are being essentially ignored by experimentalists, despite the fact that if they were used they would be enormously valuable for modeling postulated reactions to determine their feasibility. This project aims to reduce the size of this learning barrier by making MOPAC2012 easier to use, by developing documentation to describe what can be done, the issues involved, methods and strategies for exploring models of enzyme mechanisms, and by providing several complete worked examples, including the chymotrypsin-catalyzed hydrolysis of a peptide bond. The approach would begin with a small research project, to map out the chymotrypsin mechanism. Any software problems encountered would be addressed at this point. Various strategies for exploring the mechanism would be examined, and, using the results, a recommended set of procedures would be generated as documentation for use by experimentalists. Experimentalists would then use the resulting program and documentation to model reactions and phenomena in systems of interest, and their feedback would be used in improving the product. A few cycles of modeling and feedback would yield a product that should be an acceptable tool for the experimental research community for modeling enzyme mechanisms.
The task of designing new pharmaceuticals can be aided by a computer-assisted model of enzyme mechanism that would be easy to use. A program to do this, MOPAC2012, already exists, but currently it is only being used by expert computational chemists. The objective is to modify the MOPAC2012 program and its documentation to make it suitable for use by experimentalists.
