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General Outline

We are engaged in theoretical and computational investigations of complex chemical and biological systems in solution with atomic detail. Besides molecular dynamics (MD) simulations and dielectric continuum models in conjunction with quantum chem­is­try, we focus methodically on liquid state theory for modeling solvation ef­fects. Our characteristic conceptual platform is integral equation theory in various flavors. Numerical solutions to these theories yield approximate distribution functions, for instance for solvent particles around solute mol­ecules or near interfaces. From these data we can compute various structural and thermodynamic properties. The methods are specifically designed to work in conjunction with quantum chem­is­try (to account for electronic response upon solvation) and molecular dynamics (MD) simulations (to consider conformational flexibility of species in solution). Applications range from organic chem­is­try in aqueous and nonaqueous solution up to problems in biophysics and drug development.

© CCB​/​TU Dort­mund
3D RISM (reference interaction site model) results for benzene and hexafluorobenzene in their respective solution environments.


Conceptual and numerical developments for integral equation theories

We try to systematically understand and improve the approximations involved with integral equation theories as well as the numerical difficulties associated with their numerical solution on large three-dimensional grids. In particular, we ask for fundamental relations to derive the free energy of liquids and solvated species from knowledge of the solute-solvent interactions described at the same level of detail as employed in MD simulations. A range of exact results have been obtained in the past to allow for further developing the methods with the ultimate goal to reach quantitative agreement with MD results at a fraction of computational cost.

Quantum chem­is­try in solution and in heterogeneous systems

Electronic structure calculations are combined with integral equation theory by our “embedded cluster reference interaction site model” (EC-RISM) in order to arrive at a tractable and predictive theory for solvent and environmental ef­fects on chemical reactivity. Briefly, electronic and liquid structure are computed self-consistently by mapping the solvent charge distribution onto discrete point charges which polarize the electronic Hamiltonian. We obtain the solvent distribution and associated correlation functions to deduce the solvation free energy along with a molecule’s wave function in solution, from which electronic properties can be derived. Typical applications (to be detailed below) range from predictions of aqueous and nonaqueous acidities (pKa) and tautomer equilibria in homogeneous solution or near interfaces up to estimating the electronic response of solute species exposed to extreme thermodynamic conditions.

© CCB​/​TU Dort­mund
EC-RISM prediction of the differences of solvent structure around acetic and trifluoroacetic acid in water.

Chem­is­try and physicochemical properties of small drug-like mol­ecules

A key problem in medicinal chem­is­try and drug development is related to predicting physicochemical properties such as acidity constants and distribution coefficients between aqueous and nonaqueous phases, coupled to the chemical problem of characterizing the relevance or population of certain tautomeric and conformational states. To this end, EC-RISM calculations can be employed, assessing the quality of which require benchmarking against experimental data. A statistically sound measure of prediction quality is provided by blind prediction contests such as the SAMPL series. Our latest contributions to these challenges involve tautomer abundance prediction and pH-dependent distribution coefficient calculations (log D) between aqueous and nonaqueous phases.

Spectroscopic properties of solvated species

The availability of a solvent-modulated electronic wave function of a solute molecule from EC-RISM calculations allows for the determination of wave function-derived spectroscopic features. We specifically target NMR parameter prediction in solution under varying conditions in order to determine the impact of the environment. This way, it is possible to distinguish conformational from solvation ef­fects such that structure determination in solution becomes more reliable. Solvation ef­fects on vibrational modes to be studied by IR spectroscopy are also an im­por­tant area of re­search, where the challenge is to account for nonequilibrium ef­fects from a theory of the equilibrium state.

Chem­is­try at extreme conditions

Extreme thermodynamic conditions such as high hydrostatic pressure are parameters to modulate chemical and biological systems in a way not possible under ambient temperature and pressure. Studying systems at extreme conditions is furthermore re­le­vant for understanding the essential features of life-forming compounds and their adaptive capabilities. We developed special EC-RISM techniques in collaboration with theoretical and experimental groups that allow for reliable calculations of electronic structure at high pressure. From these data it is possible to derive high pressure-optimized force fields for further MD simulations and for studying the impact of extreme conditions on spectroscopic features.

Ion channel function

Channel proteins, embedded in lipid bilayers, are studied by ex­ten­sive MD simulations in combination with integral equation analyses of ion distributions in order to identify correlations between sequence and conductance/selectivity properties. A particularly difficult question is how and why the protein switches between conformational states of varying conductance ("gating"). Typical simulation systems contain on the order of 105 atoms and are computed over several hundreds of nanoseconds. The combination of MD and RISM theory allows for tackling the combined problem of conformational variability and preference for certain ion species. We apply the methodology for instance to potassium channels such as the miniature channel protein Kcv and derivatives that are experimentally studied by G. Thiel at TU Darmstadt/Germany.

© CCB​/​TU Dort­mund
The Kcv potassium channel embedded in a fully solvated DMPC membrane.

Protein-ligand binding

Integral equation calculations for the solvent degrees of freedom are applied in conjunction with MD simulations for proteins and ligands. This model is currently developed for drug development purposes in collaboration with industrial partners via affinity prediction, binding pose ranking and local hydration analysis. Results are benchmarked against experimental data provided by collaboration partners and against explicit-solvent free energy simulations. More specifically, the key question of “displaceable water” sites that can be targeted by a ligand can be addressed by an integral equation approach without suffering from sampling problems frequently encountered with MD for low-occupancy regions. A recent development, “binding free energy derivatives”, allows for defining a search direction in “chemical parameter space” that aims at rationally finding ligand chem­is­try variations that optimize the binding affinity.

Location & approach

The campus of TU Dort­mund Uni­ver­sity is located close to interstate junction Dort­mund West, where the Sauerlandlinie A 45 (Frankfurt-Dort­mund) crosses the Ruhrschnellweg B 1 / A 40. The best interstate exit to take from A 45 is "Dort­mund-Eichlinghofen" (closer to Cam­pus Süd), and from B 1 / A 40 "Dort­mund-Dorstfeld" (closer to Cam­pus Nord). Signs for the uni­ver­si­ty are located at both exits. Also, there is a new exit before you pass over the B 1-bridge leading into Dort­mund.

To get from Cam­pus Nord to Cam­pus Süd by car, there is the connection via Vo­gel­pothsweg/Baroper Straße. We recommend you leave your car on one of the parking lots at Cam­pus Nord and use the H-Bahn (suspended monorail system), which conveniently connects the two campuses.

TU Dort­mund Uni­ver­sity has its own train station ("Dort­mund Uni­ver­si­tät"). From there, suburban trains (S-Bahn) leave for Dort­mund main station ("Dort­mund Hauptbahnhof") and Düsseldorf main station via the "Düsseldorf Airport Train Station" (take S-Bahn number 1, which leaves every 20 or 30 minutes). The uni­ver­si­ty is easily reached from Bo­chum, Essen, Mülheim an der Ruhr and Duis­burg.

You can also take the bus or subway train from Dort­mund city to the uni­ver­si­ty: From Dort­mund main station, you can take any train bound for the Station "Stadtgarten", usually lines U41, U45, U 47 and U49. At "Stadtgarten" you switch trains and get on line U42 towards "Hombruch". Look out for the Station "An der Palmweide". From the bus stop just across the road, busses bound for TU Dort­mund Uni­ver­sity leave every ten minutes (445, 447 and 462). Another option is to take the subway routes U41, U45, U47 and U49 from Dort­mund main station to the stop "Dort­mund Kampstraße". From there, take U43 or U44 to the stop "Dort­mund Wittener Straße". Switch to bus line 447 and get off at "Dort­mund Uni­ver­si­tät S".

The H-Bahn is one of the hallmarks of TU Dort­mund Uni­ver­sity. There are two stations on Cam­pus Nord. One ("Dort­mund Uni­ver­si­tät S") is directly located at the suburban train stop, which connects the uni­ver­si­ty directly with the city of Dort­mund and the rest of the Ruhr Area. Also from this station, there are connections to the "Technologiepark" and (via Cam­pus Süd) Eichlinghofen. The other station is located at the dining hall at Cam­pus Nord and offers a direct connection to Cam­pus Süd every five minutes.

The AirportExpress is a fast and convenient means of transport from Dort­mund Airport (DTM) to Dort­mund Central Station, taking you there in little more than 20 minutes. From Dort­mund Central Station, you can continue to the uni­ver­si­ty campus by interurban railway (S-Bahn). A larger range of in­ter­na­tio­nal flight connections is offered at Düsseldorf Airport (DUS), which is about 60 kilometres away and can be directly reached by S-Bahn from the uni­ver­si­ty station.

The facilities of TU Dort­mund Uni­ver­sity are spread over two campuses, the larger Cam­pus North and the smaller Cam­pus South. Additionally, some areas of the uni­ver­si­ty are located in the adjacent "Technologiepark".

Site Map of TU Dort­mund Uni­ver­sity (Second Page in English).