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Biomedical subjects

W Wenzel

Publications and source records attributed to W Wenzel.

At least 19 recordsLinked to original sources
PubMed2006

A new ligand field approach to linear transition metal dihalides.

We have performed theoretical multiconfigurational calculations of the molecular energy levels based on two axial ligand field models and determined the model parameters to reproduce ab initio energies of TiCl(2), TiF(2), VCl(2), and VF(2). We develop two extensions to ligand field theory (LFT) for linear transition metal dihalides, which are incorrectly described by standard LFT. The standard LFT is augmented (1) by including the ligand induced hybridization of the d(sigma) orbital with the 4s orbital or (2) by using a different radial part for the d(sigma) orbital. Both models reproduce the energies of the first electronic states in very good agreement with numerical multireference configuration interaction results. Furthermore the model parameters are very close to experimental known Racah parameters describing the term energies of Ti(2+) and V(2+).

Journal Article↗
PubMed2006

An evolutionary strategy for all-atom folding of the 60-amino-acid bacterial ribosomal protein l20.

We have investigated an evolutionary algorithm for de novo all-atom folding of the bacterial ribosomal protein L20. We report results of two simulations that converge to near-native conformations of this 60-amino-acid, four-helix protein. We observe a steady increase of "native content" in both simulated ensembles and a large number of near-native conformations in their final populations. We argue that these structures represent a significant fraction of the low-energy metastable conformations, which characterize the folding funnel of this protein. These data validate our all-atom free-energy force field PFF01 for tertiary structure prediction of a previously inaccessible structural family of proteins. We also compare folding simulations of the evolutionary algorithm with the basin-hopping technique for the Trp-cage protein. We find that the evolutionary algorithm generates a dynamic memory in the simulated population, which leads to faster overall convergence.

Algorithms↗
PubMed2006

Basin hopping simulations for all-atom protein folding.

We investigate different protocols of the basin hopping technique for de novo protein folding. Using the protein free-energy force field PFF01 we report the reproducible all-atom folding of the 20-amino-acid tryptophan-cage protein [Protein Data Bank (PDB) code: 112y] and of the recently discovered 26-amino-acid potassium channel blocker (PDB code: 1wqc), which exhibits an unusual fold. We find that simulations with increasing cycle length and random starting temperatures perform best in comparison with other parametrizations. The basin hopping technique emerges as a simple but very efficient and robust workhorse for all-atom protein folding.

Computer Simulation↗
PubMed2005

Investigation of a Kubo-formula-based approach to estimate DNA conductance in an atomistic model.

A novel approach to estimate DNA conductance based upon Kubo formula is presented and discussed. Using this approach, the effects of base pair mismatches, different conformational changes and base pair sequence on DNA electrical properties were investigated. The results were compared with the data from other methods. The new approach makes possible very fast estimation of conductance spectra for oligonucleotides with hundreds of base pairs and can easily be extended to treat arbitrary chemical modifications of DNA.

Base Pair Mismatch↗
PubMed2005

Multireference calculations of the electronic structure of VF2 and VCl2.

We investigated the electronic structure of two members of the transition-metal dihalide family, VF(2) and VCl(2). Using the configuration-interaction method in large basis sets we calculated the lowest 17 states of these molecules in the vicinity of their ground-state geometry. We compute the ground-state bond lengths, vibrational frequencies, and dissociation energies. In contrast to predictions of ligand-field theory, we find (4)Sigma(g) (-) ground states for both molecules.

Journal Article↗
PubMed2005

Improved implementation and application of the individually selecting configuration interaction method.

We report on the progress of our implementation of the configuration-selecting multireference configuration interaction method on massively parallel architectures with distributed memory, which now permits the treatment of Hilbert spaces of dimension O(10(12)). Of these about 50,000,000 can be selected in the variational subspace. We provide scaling data for the running time of the code for the IBM/SP3 and the CRAY-T3E. We present benchmark results for two selected applications: the energetics of the isomers of dinitrosoethylene and the benchmark results for the ring closure reaction of enediyene.

Journal Article↗
PubMed2005

In silico folding of a three helix protein and characterization of its free-energy landscape in an all-atom force field.

We report the reproducible first-principles folding of the 40 amino-acid, three-helix headpiece of the HIV accessory protein in a recently developed all-atom free-energy force field. Six of 20 simulations using an adapted basin-hopping method converged to better than 3 A backbone rms deviation to the experimental structure. Using over 60 000 low-energy conformations of this protein, we constructed a decoy tree that completely characterizes its folding funnel.

Amino Acid Sequence↗
PubMed2004

All-atom folding of the three-helix HIV accessory protein with an adaptive parallel tempering method.

All-atom protein structure prediction from the amino acid sequence alone remains an important goal of biophysical chemistry. Recent progress in force field development and validation suggests that the PFF01 free-energy force field correctly predicts the native conformation of various helical proteins as the global optimum of its free-energy surface. Reproducible protein structure prediction requires the availability of efficient optimization methods to locate the global minima of such complex potentials. Here we investigate an adapted version of the parallel tempering method as an efficient parallel stochastic optimization method for protein structure prediction. Using this approach we report the reproducible all-atom folding of the three-helix 40 amino acid HIV accessory protein from random conformations to within 2.4 A backbone RMS deviation from the experimental structure with modest computational resources.

Computer Simulation↗
PubMed2004

Fluctuation analysis and accuracy of a large-scale in silico screen.

Using a cascadic version of the stochastic tunneling method we perform an all-atom database screen over 186,000 flexible ligands of the NCI 3D database against the thymidine kinase receptor. By analyzing the errors in the binding energy we demonstrate how the cascadic technique is superior to conventional sequential docking techniques and how reliable results for the determination of the top-scoring ligands could be achieved. The substrate corresponding to the crystal structure used in the screen ranks in the upper 0.05% of the database, validating both docking methodology and the applicability of the scoring function to this substrate. Several high ranking ligands of the database display significant structural similarity with known substrates. A detailed analysis of the accuracy of the screening method is carried out, and its dependence on the flexibility of the ligand is quantified.

Journal Article↗
PubMed2004

An all-atom force field for tertiary structure prediction of helical proteins.

We have developed an all-atom free-energy force field (PFF01) for protein tertiary structure prediction. PFF01 is based on physical interactions and was parameterized using experimental structures of a family of proteins believed to span a wide variety of possible folds. It contains empirical, although sequence-independent terms for hydrogen bonding. Its solvent-accessible surface area solvent model was first fit to transfer energies of small peptides. The parameters of the solvent model were then further optimized to stabilize the native structure of a single protein, the autonomously folding villin headpiece, against competing low-energy decoys. Here we validate the force field for five nonhomologous helical proteins with 20-60 amino acids. For each protein, decoys with 2-3 A backbone root mean-square deviation and correct experimental Cbeta-Cbeta distance constraints emerge as those with the lowest energy.

Algorithms↗
PubMed2003

Reproducible protein folding with the stochastic tunneling method.

We report the reproducible folding of the 20 amino-acid protein trp cage using a novel version of the stochastic tunneling method and a recently developed all-atom protein free-energy force field. Six of 25 simulations reached an energy within 1 kcal/mol of the best energy, all of which correctly predicted the native experimental structure of the protein, in total eight simulations converged to the native structure. We find a strong correlation between energy and root-mean-square deviation to the native structure for all simulations.

Computer Simulation↗
PubMed2003

Comparative analysis on the genetic relatedness of Sorghum bicolor accessions from Southern Africa by RAPDs, AFLPs and SSRs.

In order to get an overview on the genetic relatedness of sorghum (Sorghum bicolor) landraces and cultivars grown in low-input conditions of small-scale farming systems, 46 sorghum accessions derived from Southern Africa were evaluated on the basis of amplified fragment length polymorphism (AFLPs), random amplified polymorphic DNAs (RAPDs) and simple sequence repeats (SSRs). By this approach all sorghum accessions were uniquely fingerprinted by all marker systems. Mean genetic similarity was estimated at 0.88 based on RAPDs, 0.85 using AFLPs and 0.31 based on SSRs. In addition to this, genetic distance based on SSR data was estimated at 57 according to a stepwise mutation model (Deltamu-SSR). All UPGMA-clusters showed a good fit to the similarity estimates (AFLPs: r = 0.92; RAPDs: r = 0.88; SSRs: r = 0.87; Deltamu-SSRs: r = 0.85). By UPGMA-clustering two main clusters were built on all marker systems comprising landraces on the one hand and newly developed varieties on the other hand. Further sub-groupings were not unequivocal. Genetic diversity (H, DI) was estimated on a similar level within landraces and breeding varieties. Comparing the three approaches to each other, RAPD and AFLP similarity indices were highly correlated (r = 0.81), while the Spearman's rank correlation coefficient between SSRs and AFLPs was r = 0.57 and r = 0.51 between RAPDs and SSRs. Applying a stepwise mutation model on the SSR data resulted in an intermediate correlation coefficient between Deltamu-SSRs and AFLPs (r = 0.66) and RAPDs ( r = 0.67), respectively, while SSRs and Deltamu-SSRs showed a lower correlation coefficient (r = 0.52). The highest bootstrap probabilities were found using AFLPs (56% on average) while SSR, Deltamu-SSR and RAPD-based similarity estimates had low mean bootstrap probabilities (24%, 27%, 30%, respectively). The coefficient of variation (CV) of the estimated genetic similarity decreased with an increasing number of bands and was lowest using AFLPs.

Africa, Southern↗
PubMed2003

Current collapse in tunneling transport through benzene.

We investigate the electrical transport through a system of benzene coupled to metal electrodes by electron tunneling. Using electronic structure calculations, a semiquantitative model for the pi electrons of the benzene is derived that includes general two-body interactions. After exact diagonalization of the benzene model the transport is computed using perturbation theory for weak electrode-benzene coupling (golden rule approximation). We include the effect of an applied electric field on the molecular states, as well as radiative relaxation. We predict a current collapse and strong negative differential conductance due to a "blocking" state when the electrode is coupled to the para-position of benzene. In contrast, for coupling to the meta-position, a series of steps in the I-V curve is found.

Journal Article↗
PubMed2002

Disorder induced quantum phase transition in random-exchange spin-1/2 chains.

We investigate the effect of quenched bond disorder on the anisotropic antiferromagnetic spin-1/2 (XXZ) chain as a model for disorder-induced quantum phase transitions. We find nonuniversal behavior of the average correlation functions for weak disorder, followed by a quantum phase transition into a strongly disordered phase with only short-range xy correlations. We find no evidence for the universal strong-disorder fixed point predicted by the real-space renormalization group, suggesting a qualitatively different view of the relationship between quantum fluctuations and disorder.

Journal Article↗
PubMed2002

Electrical transport through single-molecule junctions: from molecular orbitals to conduction channels.

We present an atomistic theory of electronic transport through single organic molecules that reproduces the important features of the current-voltage ( I-V) characteristics observed in recent experiments. We trace these features to their origin in the electronic structure of the molecules and their local atomic environment. We demonstrate how conduction channels arise from the molecular orbitals and elucidate the contributions of individual orbitals to the current. We find that in thiol-bridged aromatic molecules many molecular orbitals contribute to a single conduction channel and discuss the implications of this result for the design of molecular devices.

Journal Article↗
PubMed2000

[Current classification of anti-arrhythmia agents].

Antiarrhythmic drugs can be divided into four Vaughan Williams classes (I-IV) according to defined electrophysiological effects on the myocardium. Thus, the Vaughan Williams classification also coincides with the main myocardial targets of the antiarrhythmics, i.e., myocardial sodium-, potassium-, and calcium-channels or beta-adrenergic receptors. A more detailed characterization which is also based on the myocardial targets of a drug is given by the "Sicilian Gambit" approach of classification. Nevertheless, the appropriate drug for the management of a given clinical arrhythmia has to be chosen according to the electrophysiological effects of the respective drug. A main determinant of the antiarrhythmic or proarrhythmic properties of a drug is the frequency dependence of its electrophysiological effects. The sodium-channel blockade induced by class-I substances is enhanced with increasing heart rates. Thus, class-I antiarrhythmics can be subclassified as substances showing a more exponential, an approximately linear, or rather saturated block-frequency relation. Class-III antiarrhythmics (potassium-channel blockade) can be further differentiated according to the component of the delayed rectifier potassium current (IK) which is inhibited by a drug. Class-III drugs inhibiting selectively the rapidly activating and deactivating IKr component exhibit a marked reverse rate dependence, i.e., the drug induced prolongation of the cardiac action potential is minimized at high rates. On the other hand, during bradycardia the pronounced action potential prolongation may cause early afterdepolarizations and triggered activity leading to torsades de pointes arrhythmias (acquired QT syndrome). Class-III substances inhibiting the slowly activating IKs component are currently under investigation and are expected to show a direct rate dependence. Experimental data available so far point to an action potential prolonging effect at least independent of rate. However, it is uncertain whether proarrhythmic effects can be thus avoided, especially in light of the fact that one form of congenital QT syndrome (LQT1) seems to be linked to dysfunction of the IKs-channel.

Adrenergic beta-Antagonists↗