Theoretical studies to characterize inhibition mechanisms and ligand-target complexes
Prof. Dr. Bernd Engels
To clarify the mechanisms of action and for the development of new antiinfectivesi n the TP C3 we perform theoretical investigations in two directions.
First, the mechanisms of action of inhibitors will be investigated, which block their targets irreversibly by the formation of a new covalent bond. To achieve this we apply combined Quantum mechanics/Molecular Modeling (QM/MM) methods in the determination of the inhibition mechanism of cysteine proteases and of inhibitors that contain Michael-systems as electrophilic building block.
This approach allows us the explicit inclusion of effects of the protein surroundings, solvent effects in the calculation and the description of covalent bond breaking and forming in macromolecular systems like enzymes. This work is important for the TP A4 and B2.
Self assembly by molecular recognition plays an important role in the research on biochemical processes and the structure based drug design. "Teilbereich" C3 is able to characterize intermolecular interactions (i.e. van-der-Waals interactions, Hydrogen bonds, electrostatic interactions or salt bridges) and intermolecular interactions (e.g. rigidity) with the aid of theoretical chemistry. Our investigations are on the self assembly of derivates of guanidiniocarbonylpyrrols (TP A3, C1). Here, it is necessary to account for the conformative properties of a system, and to find all important local and the global minimum on the potential energy surface. For this purpose our working group develops and applies new procedures for the conformational search. The computations showed that the high stability of the guanidiniocarbonylpyrrol dimers comes from the rigidity of the system up to 50%. New optimization algorithm based on the Tabu-Search. By applying the gradients and a couple of additional improvements we got an algorithm that performed much better on well known test functions than every other algorithm we know. This Tabu-Search algorithm now should be adapted and applied on questions relevant to the SFB (like the conformational search)
Selected SFB-relevant Publications
W. Lee, B. Engels; The Protonation State of Catalytic Residues in the Resting State of KasA Revisited: Detailed Mechanism for the Activation of KasA by Its Own Substrate. Biochemistry 2014, 53, 919-931. doi:10.1021/bi401308j
W. Lee, B. Engels; Clarification on the Decarboxylation Mechanism in KasA Based on the Protonation State of Key Residues in the Acyl-Enzyme State. J Phys Chem B 2013, 117, 8095-8104. doi:10.1021/jp403067m
K. Ansorg, M. Tafipolsky, B. Engels; Cation-pi Interactions: Accurate Intermolecular Potential from Symmetry-Adapted Perturbation Theory. J Phys Chem B 2013. doi:10.1021/jp403578r
W. Lee, S. R. Luckner, C. Kisker, P. J. Tonge, B. Engels; Elucidation of the protonation states of the catalytic residues in mtKasA: implications for inhibitor design. Biochemistry 2011, 50, 5743-5756.
S. Schlund, E. M. B. Janke, K. Weisz, B. Engels; Predicting the Tautomeric Equilibrium of Acetylacetone in Solution. I. The Right Answer for the Wrong Reason? Journal of Computational Chemistry 2010, 31, 665-670.
A. Paasche, M. Schiller, T. Schirmeister, B. Engels; Mechanistic Study of the Reaction of Thiol-Containing Enzymes with alpha,beta-Unsaturated Carbonyl Substrates by Computation and Chemoassays. Chemmedchem 2010, 5, 869-880.
S. Stepanenko, B. Engels; Tabu Search Based Strategies for Conformational Search. Journal of Physical Chemistry A 2009, 113, 11699-11705.
M. Mladenovic, M. Arnone, R. F. Fink, B. Engels; Environmental Effects on Charge Densities of Biologically Active Molecules: Do Molecule Crystal Environments Indeed Approximate Protein Surroundings? Journal of Physical Chemistry B 2009, 113, 5072-5082.
E. M. B. Janke, S. Schlund, A. Paasche, B. Engels, R. Dede, I. Hussain, P. Langer, M. Rettig, K. Weisz; Tautomeric Equilibria of 3-Formylacetylacetone: Low-Temperature NMR Spectroscopy and ab Initio Calculations. Journal of Organic Chemistry 2009, 74, 4878-4881.
V. Buback, M. Mladenovic, B. Engels, T. Schirmeister; Rational Design of Improved Aziridine-Based Inhibitors of Cysteine Proteases. Journal of Physical Chemistry B 2009, 113, 5282-5289.
A. Paasche, M. Arnone, R. F. Fink, T. Schirmeister, B. Engels; Origin of the Reactivity Differences of Substituted Aziridines: CN vs CC Bond Breakages. Journal of Organic Chemistry 2009, 74, 5244-5249.
S. Schlund, R. Muller, C. Grassmann, B. Engels; Conformational analysis of arginine in gas phase - A strategy for scanning the potential energy surface effectively. Journal of Computational Chemistry 2008, 29, 407-415.
S. Stepanenko, B. Engels; New Tabu Search based global optimization methods outline of algorithms and study of efficiency. Journal of Computational Chemistry 2008, 29, 768-780.
M. Mladenovic, R. F. Fink, W. Thiel, T. Schirmeister, B. Engels; On the origin of the stabilization of the zwitterionic resting state of cysteine proteases: A theoretical study. Journal of the American Chemical Society 2008, 130, 8696-8705.
M. Mladenovic, K. Ansorg, R. F. Fink, W. Thiel, T. Schirmeister, B. Engels; Atomistic insights into the inhibition of cysteine proteases: First QM/MM calculations clarifying the stereoselectivity of epoxide-based inhibitors. Journal of Physical Chemistry B 2008, 112, 11798-11808.
M. Mladenovic, K. Junold, R. F. Fink, W. Thiel, T. Schirmeister, B. Engels; Atomistic insights into the inhibition of cysteine proteases: First QM/MM calculations clarifying the regiospecificity and the inhibition potency of epoxide- and aziridine-based inhibitors. Journal of Physical Chemistry B 2008, 112, 5458-5469.
S. Stepanenko, B. Engels; Gradient tabu search. Journal of Computational Chemistry 2007, 28, 601-611.
S. Schlund, C. Schmuck, B. Engels; How important is molecular rigidity for the complex stability of artificial host-guest systems? A theoretical study on self-assembly of gas-phase arginine. Chemistry-a European Journal 2007, 13, 6644-6653.
M. Mladenovic, T. Schirmeister, S. Thiel, W. Thiel, B. Engels; The importance of the active site histidine for the activity of epoxide- or aziridine-based inhibitors of cysteine proteases. Chemmedchem 2007, 2, 120-128.