Optimization of Artificial Keto-Reductases Based on the Biotin-Avidin
Technology: Theoretical and Practical Aspects

In the past three decades, homogeneous and enzymatic catalysis have
evolved independently to provide the necessary tools for the synthesis
of high value added products. These two approaches are complementary
in many respects. With the aim of exploiting the advantages of both
fields, artificial metalloenzymes have recently attracted increasing
attention. Such hybrid catalysts result from combining an
organometallic moiety, typical of homogeneous catalysts, with a
protein, reminiscent of an enzyme. Following this approach, several
artificial metalloenzymes have been designed, optimized and
structurally characterized.

Within this project, it is proposed to combining both in-silico
(computer-based) and in-vitro (experiment) screening of artificial
metalloenzymes. For this purpose, mixed quantum mechanical/classical
mechanics (QM/MM) calculations of artificial ketoreductases based on
the biotin-avidin technology will be carried out. Because QM/MM is
computationally a very demanding technique, also force field-based
approaches will be further developed. One of them - VALBOND-TRANS - is
specifically designed for treating metal centers in particular bonding
topologies. Until now, VT has only been parametrized for octahedral
complexes and we seek to extend this to square planar compounds.
Finally, the insight obtained from the computational studies will be
applied towards the chemogenetic optimization of artificial
keto-reductases

This project aims at providing alternative catalytic solutions with
potentially broad (industrial) applications. Artifical enzymes have
the potential to combine some of the attractive features of both
homogeneous and enzymatic catalysis. Here we try to pursue a targeted
approach that is inspired by how nature addresses such problems and
that is guided by reliable computations.