Project

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

English title Optimization of Artificial Keto-Reductases Based on the Biotin-Avidin Technology: Theoretical and Practical Aspects
Applicant Meuwly Markus
Number 127457
Funding scheme ProDoc
Research institution Physikalische Chemie Departement Chemie Universität Basel
Institution of higher education University of Basel - BS
Main discipline Physical Chemistry
Start/End 01.09.2009 - 31.08.2012
Approved amount 344'608.00
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All Disciplines (2)

Discipline
Physical Chemistry
Inorganic Chemistry

Keywords (10)

catalysis; biomimetic; trans effect; x-ray; ligand binding; QM/MM simulation; computational chemistry; force fields; biotin-avidintechnology; metalloenzymes

Lay Summary (English)

Lead
Lay summary
In the past three decades, homogeneous and enzymatic catalysis haveevolved independently to provide the necessary tools for the synthesisof high value added products. These two approaches are complementaryin many respects. With the aim of exploiting the advantages of bothfields, artificial metalloenzymes have recently attracted increasingattention. Such hybrid catalysts result from combining anorganometallic moiety, typical of homogeneous catalysts, with aprotein, reminiscent of an enzyme. Following this approach, severalartificial metalloenzymes have been designed, optimized andstructurally characterized.

Within this project, it is proposed to combining both in-silico(computer-based) and in-vitro (experiment) screening of artificialmetalloenzymes. For this purpose, mixed quantum mechanical/classicalmechanics (QM/MM) calculations of artificial ketoreductases based onthe biotin-avidin technology will be carried out. Because QM/MM iscomputationally a very demanding technique, also force field-basedapproaches will be further developed. One of them - VALBOND-TRANS - isspecifically designed for treating metal centers in particular bondingtopologies. Until now, VT has only been parametrized for octahedralcomplexes and we seek to extend this to square planar compounds.Finally, the insight obtained from the computational studies will beapplied towards the chemogenetic optimization of artificialketo-reductases

This project aims at providing alternative catalytic solutions withpotentially broad (industrial) applications. Artifical enzymes havethe potential to combine some of the attractive features of bothhomogeneous and enzymatic catalysis. Here we try to pursue a targetedapproach that is inspired by how nature addresses such problems andthat is guided by reliable computations.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Computational Organometallic Chemistry with Force Fields
J. Huang, M. Devereux, F. Hofmann, M. Meuwly (2012), Computational Organometallic Chemistry with Force Fields, in Y. Wu and O. Wiest (ed.), Springer, Heidelberg, 19-47.
Ligand Self-Assembling through Complementary Hydrogen-Bonding in the Coordination Sphere of a Transition Metal Center: The 6-Diphenylphosphanylpyridin-2(1H)-one System
Gellrich U, Huang J, Seiche W, Keller M, Meuwly M, Breit B (2011), Ligand Self-Assembling through Complementary Hydrogen-Bonding in the Coordination Sphere of a Transition Metal Center: The 6-Diphenylphosphanylpyridin-2(1H)-one System, in JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 133(4), 964-975.
Human Carbonic Anhydrase II as a host for piano-stool complexes bearing a sulfonamide anchor
Monnard FW, Heinisch T, Nogueira ES, Schirmer T, Ward TR, Human Carbonic Anhydrase II as a host for piano-stool complexes bearing a sulfonamide anchor, in CHEMICAL COMMUNICATIONS, 47(29), 8238-8240.
Hydrogen-Bond and Solvent Dynamics in Transition Metal Complexes
J. Huang, D. Haeussinger, U. Gellrich, W. Seiche, B. Breit, M. Meuwly, Hydrogen-Bond and Solvent Dynamics in Transition Metal Complexes, in J. Phys. Chem B.

Collaboration

Group / person Country
Types of collaboration
University of Freiburg/Br Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Fall Meeting Swiss Chemical Society 14.09.2012 Zuerich
CCROS - Catalysts and Catalytic Reactions for Organic Synthesis 02.09.2012 Rheinfelden / D
Fall Meeting Swiss Chemical Society 09.09.2011 Lausanne
CHARMM Meeting 2011 15.07.2011 Madison, WI
25th Molecular Modelling Workshop 05.04.2011 Erlangen


Abstract

Traditionally, catalysis has been divided into three areas: homogeneous, enzymatic and heterogeneous. With the aim of complementing these methodologies, artificial metalloenzymes have attracted increasing attention in recent years. Artificial metalloenzymes result from combining an active organometallic moiety with a macromolecular host (protein or DNA). In this context, we have been using the biotin-avidin technology to produce artificial metalloenzymes for various catalytic enantioselective transformations: hydrogenation, transfer hydrogenation, allylic alkylation and sulfoxidation. Thus far, the focus was proof-of-principle studies using model substrates.Within the context of the International Research Training Network 1038: ?Catalysts and Catalytic Reactions for Organic Synthesis?, a joint trans-national Graduiertenkolleg has been approved by the DFG. In collaboration with the groups of Profs. Brückner and Müller, the current project aims at optimizing the performance of artificial keto-reductases for the selective reduction of (poly)keto-esters. With this goal in mind, it is proposed to explore either hydrogenation or transfer-hydrogenation catalysts based on biotinylated Ru-complexes inspired from known homogeneous systems. As the enantioselection mechanim is dictated by second coordination sphere interactions, we anticipate that artificial keto-reductases will allow to produce enantio- and diastereomers, difficult to obtain using either homogeneous- or enzymatic systems.To this end, a unified approach, combining both in-silico and in-vitro screening of artificial metalloenzymes will be pursued. For this purpose, it is proposed that three graduate students at the University of Basel join forces and focus on i) QM-MM modelling of artificial keto-reductases based on the biotin-avidin technology (joint supervision Profs. Meuwly and Ward); ii) parametrizing the trans-effect in CHARMM will be carried out by a second graduate student supervised by Prof. M. Meuwly. iii) The insight obtain from modelling will be applied towards the chemogenetic optimization of artificial keto-reductases (in the group of Prof. Ward).The results obtained using artificial metalloenzymes will systematically be compared with the results obtained in the groups of Profs. Brückner (homogeneous catalysis) and Müller (enzymatic catalysis) for the selected substrates.
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