Showing papers by "Hans-Peter Lenhof published in 2002"

A combinatorial approach to protein docking with flexible side chains.

Abstract: Rigid-body docking approaches are not sufficient to predict the structure of a protein complex from the unbound (native) structures of the two proteins. Accounting for side chain flexibility is an important step towards fully flexible protein docking. This work describes an approach that allows conformational flexibility for the side chains while keeping the protein backbone rigid. Starting from candidates created by a rigid-docking algorithm, we demangle the side chains of the docking site, thus creating reasonable approximations of the true complex structure. These structures are ranked with respect to the binding free energy. We present two new techniques for side chain demangling. Both approaches are based on a discrete representation of the side chain conformational space by the use of a rotamer library. This leads to a combinatorial optimization problem. For the solution of this problem, we propose a fast heuristic approach and an exact, albeit slower, method that uses branch-and-cut techniques. As a test set, we use the unbound structures of three proteases and the corresponding protein inhibitors. For each of the examples, the highest-ranking conformation produced was a good approximation of the true complex structure.

BioMiner--modeling, analyzing, and visualizing biochemical pathways and networks.

Abstract: MOTIVATION Understanding the biochemistry of a newly sequenced organism is an essential task for post-genomic analysis. Since, however, genome and array data grow much faster than biochemical information, it is necessary to infer reactions by comparative analysis. No integrated and easy to use software tool for this purpose exists as yet. RESULTS We present a new software system--BioMiner--for analyzing and visualizing biochemical pathways and networks. BioMiner is based on a new comprehensive, extensible and reusable data model--BioCore--which can be used to model biochemical pathways and networks. As a first application we present PathFinder, a new tool predicting biochemical pathways by comparing groups of related organisms based on sequence similarity. We successfully tested PathFinder with a number of experiments, e.g. the well studied glycolysis in bacteria. Additionally, an application called PathViewer for the visualization of metabolic networks is presented. PathViewer is the first application we are aware of which supports the graphical comparison of metabolic networks of different organisms. AVAILABILITY http://www.zbi.uni-saarland.de/chair/projects/BioMiner SUPPLEMENTARY INFORMATION Additional information on experimental results can be found on our web site.

Multiple sequence alignment with arbitrary gap costs: computing an optimal solution using polyhedral combinatorics.

Abstract: Multiple sequence alignment is one of the dominant problems in computational molecular biology. Numerous scoring functions and methods have been proposed, most of which result in NP-hard problems. In this paper we propose for the first time a general formulation for multiple alignment with arbitrary gap-costs based on an integer linear program (ILP). In addition we describe a branch-and-cut algorithm to effectively solve the ILP to optimality. We evaluate the performances of our approach in terms of running time and quality of the alignments using the BAliBase database of reference alignments. The results show that our implementation ranks amongst the best programs developed so far.

Lectin-sugar interaction. Calculated versus experimental binding energies.

Abstract: Although a steadily increasing number of protein–ligand docking experiments have been performed successfully, there are only few studies concerning protein–sugar interactions. In this study, we investigate the interaction of wheat germ agglutinin (WGA) with N-acetylglucosamine and a number of its derivatives and predict the binding free energies using flexible docking techniques. To assess the quality of our predictions, we also determined those binding free energies experimentally in cell-binding studies. The predicted binding site, ligand orientation, and details of the binding mode are in perfect agreement with the known crystal structure of WGA with a sialoglycopeptide. Furthermore, we obtained an excellent linear correlation of our predicted binding free energies with both our own data and experimental data from the literature [Monsigny, M., Roche, A.C., Sene, C., Maget Dana, R. & Delmotte, F. (1980) Eur. J. Biochem.104, 147–153.]. In both cases, predicted energies were within 1.0 kJ·mol−1 of the experimental value. These results illustrate the usefulness of docking-based methods for the qualitative and quantitative prediction of protein–carbohydrate interactions. The insights gained from such theoretical studies may be used to complement the results from the still scarce crystal structures.

Calculated versus experimental binding energies

Abstract: Although a steadily increasing number of protein‐ligand docking experiments have been performed successfully, there are only few studies concerning protein‐sugar interactions. In this study, we investigate the interaction of wheat germ agglutinin (WGA) with N-acetylglucosamine and a number of its derivatives and predict the binding free energies using flexible docking techniques. To assess the quality of our predictions, we also determined those binding free energiesexperimentallyincell-bindingstudies.Thepredicted binding site, ligand orientation, and details of the binding mode are in perfect agreement with the known crystal structure of WGA with a sialoglycopeptide. Furthermore, we obtained an excellent linear correlation of our predicted binding free energies with both our own data and experi