ENZYMECH: Computer Simulation of Enzyme-Reactionmechanisms

Project summary

ENZYMECH was concerned with the cheminformatics, modeling and simulation of biological systems. The schematic diagram above shows the principles of fluorescence resonant energy transfer (FRET), which is also known as the spectroscopic ruler and is used to measure distances in proteins and other biological systems. FRET was simulated for the first time using a combination of molecular mechanics and quantum mechanical calculations. The results showed that the commonly used interpretation of FRET results can lead to large errors in measured distances.

Fundamentals: The elucidation of the mode of action of enzymes represents one of the grand challenges in modern chemistry. Enzymes represent targets for the specific development of drugs ("rational drug design") and are also important in transcriptional regulatory systems, such as the Tet-Repressor (TetR) regulatory switch. The development of new models and techniques in computational and theoretical chemistry and the development of modern computer technology allows the exploration of enzymatic and regulatory mechanisms as well as computer-aided drug design.

Goal: The aim of the ENZYMECH project is the application and the development of methods, computer programs and the simulation of the mechanisms of enzymatic and regulatory processes on different levels of theory:

Development of Ligand Based Techniques for the Elucidation of the Binding Mode in the Receptor Active Site: Drug design still suffers from a situation where the number of enzymes with known 3D structure is small compared with the number of pharmaceutically relevant enzymes. To gain insight into the geometry of the binding pocket of an enzyme for which the 3D-structure or the binding mode is unknown, a reverse approach has to be established. This technique should enable the mapping of spatial and physico-chemical properties of the enzyme's active site by comparing the binding modes of ligands that normally dock into the receptor pocket. The systematic superimposition of a series of ligands, binding to the same receptor, is performed to extract their 3D maximum common substructure (3D-MCSS) and to deduce the arrangement of pharmacophoric groups. A pharmacophore defines the 3D arrangement of functional groups or physicochemical properties within the ligands, as e.g. hydrophilic and hydrophobic areas or areas acting as H-bond acceptors or -donors, respectively. As reactions often take place in the catalytic centre on a metal ion, also metal complexes with relation to a binding pocket of an enzyme should be modelled. It is also possible to draw conclusions on details of the geometry of metal complexes by superimposition of a series of complexes. Stochastic optimisation methods like genetic algorithms (GA) are employed to handle the problem of conformational flexibility. The GA was implemented in a parallel version using the message passing interface library (MPI). This work was performed in collaboration with the local computing centre (RRZE) in Erlangen as a partnership within the KONWIHR project.

Simulation of Spectroscopic Properties of Proteins: To calculate spectroscopic properties of enzyme systems under realistic thermal conditions, we have developed a new method (MD/MO) which combines classical molecular dynamics (MD) and semiempirical molecular orbital (MO) theory. The MD simulation of the enzyme provides snapshots of the "hot" geometry of the solvated enzyme at realistic temperatures. Within periodic intervals, the spectroscopic properties of the relevant enzyme chromophores are calculated using semiempirical configuration interaction (CI) calculations. The effects of the enzyme environment and the solvent on the chromophore can be taken into account using hybrid quantum mechanical/molecular mechanical (QM/MM) methods or continuum solvation approaches.

The combined MD/MO method is used to calculate a variety of spectroscopic properties, such as absorption and fluorescence spectra. Experimentally, Förster energy transfer (fluorescence resonance energy transfer, FRET) is observed in many laser fluorescence measurements of proteins and is often used as a probe for the investigation of possible conformations of a protein. In order to investigate FRET on a molecular basis, we calculate FRET using our combined MD/MO method.

The calculated spectra and fluorescence decays are compared with experimental results to identify and characterise dynamic processes within the protein. The molecular dynamics simulations are carried out using an MPI-parallel version of the AMBER program package. For the semiempirical CI-calculations we use the semiempirical program package VAMP that was developed in Tim Clark's group.

KONWIHR funding and follow-up projects

  • initial KONWIHR funding: 01/2001 - 12/2002


  • Prof. T. Clark, Computer-Chemie-Centrum, Universität Erlangen-Nürnberg
  • Prof. J. Gasteiger, Computer-Chemie-Centrum, Universität Erlangen-Nürnberg

Selected publications

  • A. v. Homeyer: A Superimposition Method for Small Ligand Molecules: Implementation and Application, Dissertation, Naturwissenschaftliche Fakultät II, Universität Erlangen-Nürnberg, (2007). External link: E-Diss
  • F. Beierlein: QM/MM Docking and Simulations of FRET, Dissertation, Naturwissenschaftliche Fakultät II, Universität Erlangen-Nürnberg, (2005). External link: E-Diss