Analyzing the performance of conformational search programs on compound databases.

We have studied the sampling performance of conformational search programs using geometric and energetic criteria. Ideally, a conformational search algorithm should identify the largest possible number of low-energy structures (energy criterion) covering the widest possible range of molecular shapes (geometric criterion). Geometric analysis consisted in comparing the distribution of conformations within the generated ensembles by multidimensional scaling and by analysing the eigenvalue structure of the pairwise coordinate covariance matrices.

Double hydrogen tunneling revisited: the breakdown of experimental tunneling criteria.

Formic acid dimer was chosen as a model system to investigate synchronous double proton transfer by means of variational transition state theory (VTST) for various isotopically modified hydrogen species. The electronic barrier for the double proton transfer was evaluated to be 7.9 kcal/mol, thus being significantly lower than it was determined in previous studies.

C5-methylation of cytosine in B-DNA thermodynamically and kinetically stabilizes BI.

We have examined the backbone dynamics of two alternating purine-pyrimidine dodecamers. One sequence consists of "pure" GC bases; the other one contains 5-methylcytosines. The effect of the methyl groups on the backbone substates BI/BII was investigated by means of molecular dynamics.

Influence of backbone conformations of human carbonic anhydrase II on carbon dioxide hydration: hydration pathways and binding of bicarbonate.

In this study, the hydration of carbon dioxide and the formation of bicarbonate in human carbonic anhydrase II have been examined. From semiempirical QM/MM molecular dynamics studies, dominant conformations of the protein backbone, possibly contributing to the catalytic activity, have been isolated and further examined by means of density functional QM/MM methods. In agreement with experimental observations, a binding site for cyanate, which acts as an inhibitor, has been located, whereas for carbon dioxide, depending on the conformation of the protein environment, either a different binding site or no binding site has been found.

A QM-MM interface between CHARMM and TURBOMOLE: implementation and application to systems in bulk phase and biologically active systems.

The implementation of a hybrid QM-MM approach combining ab initio and density functional methods of TURBOMOLE with the molecular mechanics program package CHARMM is described. An interface has been created to allow data exchange between the two applications. With this method the efficient multiprocessor capabilities of TURBOMOLE can be utilized with CHARMM running as a single processor application.

Hydration of hydroxypyrrole influences binding of ImHpPyPy-beta-Dp polyamide to DNA.

Ligands which are able to recognize DNA sequence specifically are of fundamental interest as transcription controlling drugs. Recently a polyamide ligand was developed (ImHpPyPy-beta-Dp) which differentiates in a dimeric arrangement between all four possible base pair steps in the minor groove. This is a landmark for the design of DNA binding drugs because it was believed that such a recognition could only be possible in the major groove of DNA.

Energetic and stereochemical effects of the protein environment on substrate: a theoretical study of methylmalonyl-CoA mutase.

QM/MM methods were used to study the isomerization step from (2R)-methylmalonyl-CoA to succinyl-CoA. A pathway via a "fragmentation-recombination" mechanism is ruled out on energetic grounds. For the other radicalic pathway, involving an addition recombination step, geometries and vibrational contributions have been determined, and a barrier height of 11.