Research

Research Projects

In silico Drug Design of Indoleamine 2,3-Dioxygenase Inhibitors
Simulations of Amyloid Fibril Formation
Molecular Dynamics Simulations of Signal Transduction in Rhodopsin
Hybrid QM/MM Study of the Photoreaction in Rhodopsin
Optical Properties of Molecules in Solution via Hybrid QM/MM Simulations
Quantum Chemical Investigation of Chromphores and Polyenes under Tensile Stress
Syntheses of Phosphinine-Based Tripodal Ligands

In silico Drug Design of IDO Inhibitors

Indoleamine 2,3-dioxygenase (IDO) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. We use the evolutionary docking algorithm EADock to design new inhibitors of this enzyme. Up to date, pharmacophore-based and fragment-based in silico approaches yielded several new low-molecular weight inhibitor scaffolds, the most active being of nanomolar potency in an enzymatic assay. Cellular assays confirmed the potential biological relevance of four different scaffolds.

Simulations of Amyloid Fibril Formation

Diverse neurodegenerative diseases such as Alzheimer, Parkinson, Huntington, and prion diseases are associated with amyloid fibrils formed by various polypeptides. We study the heptapeptide Aβ16-22, which contains the central hydrophobic core of the physiologically relevant Alzheimer peptides and has been shown to form amyloid fibrils, by classical molecular dynamics and metadynamics simulations.

Molecular Dynamics Simulations of the Signal Transduction in Rhodopsin

Rhodopsin-like photoreceptors form a large family of signal-transducing proteins whose activation by light leads to a stimulation of the optical nerve. Their common structural features include a bundle of seven transmembrane helices accomodating the covalently bound chromophore. A large effort has been devoted to the understanding of the underlying activation mechanism which is of fundamental importance for the process of human vision. Our classical molecular dynamics simulations of rhodopsin suggest a possible molecular mechanism for the early steps of signal transduction in a prototypical G-protein coupled receptor.

Hybrid QM/MM Study of the Photoreaction in Rhodopsin

The primary event of vision involves the isomerization of the chromophore of rhodopsin, the protonated Schiff base of 11-cis retinal, to its all-trans form. This extremely fast and efficient process is completed within 200 fs and displays a quantum yield of 0.65. In spite of many experimental and theoretical studies the detailed mechanistic understanding remains an open question. Hybrid QM/MM simulations allow us to consider the dynamics of the chrompohore in the excited state, while the rest of the system is taken into account by a classical force field. Our simulations show that (1) the protein binding pocket selects and accelerates the isomerization exclusively around the C11-C12 bond via preformation of a twisted structure, (2) the 11-cis to all-trans isomerization is possible within the binding pocket with a minor atomic rearrangement, producing a highly strained chromophore, and (3) the photon energy in bathorhodopsin is stored in internal strain of the RPSB and in steric interaction energy with the protein. Hence, the initial step of vision can be viewed as the compression of a molecular spring that can then release its strain by altering the protein environment in a highly specific manner.

Optical Properties of Molecules in Solution via Hybrid QM/MM SimulationsThe combination of a hybrid quantum mechanical/moleculat mechanical (QM/MM) method with an excited-state algorithm such as ROKS or TDDFT was first tested on acetone in water. It is known from experiments that the first singlet excitation of acetone displays a large blueshift (+0.2 eV) in going from gas phase to a system solvated in water. By using QM/MM simulations we are able to reproduce this shift. In addition we obtain a reasonable agreement between the calculated and the experimentally measured Stokes shift, that is, the shift between the abosrption and the emission maxima. In subsequen studies, the methodology was successfully applied to biologically more important chromophores.

Quantum Chemical Investigation of Chromphores and Polyenes under Tensile Stress

Diploma Thesis with Dr. Irmgard Frank and Prof. Dr. C. Bräuchle, LMU Munich, Germany

Motivated by single molecule AFM experiments of the research group of Hermann Gaub (Physics Department, LMU Munich), we investigated the effect of tensile stress upon the optical properties of hemicyanine dyes. In addition, we simulated the behaviour of conjugated polyenes under high pulling forces with the means of Car-Parrinello molecular dynamics simulations.

Syntheses of Phosphinine-Based Tripodal Ligands

Research Project with Dr. P. Le Floch and Prof. Dr. F. Mathey, Ecole Polytechnique, Palaiseau, France

We achieved the syntheses of several tripodal phosphinine-based ligands. Reaction with [W(CO)5(THF)] yields the corresponding W(CO)3 complexes that could be structurally characterized by x-ray crystallography.

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