The emergence of the field of enzyme design, with promising advances in both directed evolution and computer aided enzyme design. The progress on this front should provide a deeper understanding of catalysis, help in controlling what a given enzyme is doing as well as the use of specialized enzymes for key applications, including pro-drug activation, novel synthesis of biochemically relevant molecules (e.g.
, chiral pharmaceuticals) and more. However, the progress in enzyme design has not yet led to designer enzymes that rival native enzymes.
Thus, it is clear that the potential of this important field can be greatly enhanced by computational approaches that actually consider the activation barriers of the reactions that are being catalyzed.
Thus we will have started to quantify computer-aided enzyme design by: (a) reproducing quantitatively the observed catalytic effects of key designer enzymes by EVB simulations1,2,3,4
(b) Using our approaches in actual enzyme design projects, including changing the action of promiscuous enzymes, improving available designer enzymes and helping in the design of new enzymes. (c) Exploring the reasons behind the finding that catalytic antibodies are usually less effective than enzymes that catalyze similar reactions.
Overall we are trying to develop more quantitative design concepts that will use the calculated contribution of different residues for transition state stabilization, and exploit our ability to quantify the preorganization effects. Thus we are advancing methods for early screening and further establish our quantitative ability in the final screening stages. We are developing coarse grained (CG) model that can be used as a reference potential for the calculations of the TS binding free energy and we will also developing and refining automated approaches that can simultaneously consider several mutations. While exploring the predicted power of our approaches we continue collaborating with research groups that are involved in actual enzyme design experiments.