Biomedical subjects

A Windemuth

Publications and source records attributed to A Windemuth.

7 recordsLinked to original sources

PubMed2001

Haplotype variation and linkage disequilibrium in 313 human genes.

Variation within genes has important implications for all biological traits. We identified 3899 single nucleotide polymorphisms (SNPs) that were present within 313 genes from 82 unrelated individuals of diverse ancestry, and we organized the SNPs into 4304 different haplotypes. Each gene had several variable SNPs and haplotypes that were present in all populations, as well as a number that were population-specific. Pairs of SNPs exhibited variability in the degree of linkage disequilibrium that was a function of their location within a gene, distance from each other, population distribution, and population frequency. Haplotypes generally had more information content (heterozygosity) than did individual SNPs. Our analysis of the pattern of variation strongly supports the recent expansion of the human population.

Alleles↗

PubMed2000

The predictive power of haplotypes in clinical response.

A variety of approaches have been proposed to find genetic markers that can be used in a clinical setting. Single nucleotide polymorphisms (SNPs) are the basis of the most commonly used approaches. Here we describe an approach using gene-based haplotypes, which are collections of SNPs located throughout the ftinctional regions of candidate genes, and organised as they occur separately on an individual's two chromosomes. The main point of this review is that the haplotype has greater power than any individual SNP to track an unobsenrved, but evolutionarily linked, variable site.

Animals↗

PubMed1999

Gene expression analysis by transcript profiling coupled to a gene database query.

We describe an mRNA profiling technique for determining differential gene expression that utilizes, but does not require, prior knowledge of gene sequences. This method permits high-throughput reproducible detection of most expressed sequences with a sensitivity of greater than 1 part in 100,000. Gene identification by database query of a restriction endonuclease fingerprint, confirmed by competitive PCR using gene-specific oligonucleotides, facilitates gene discovery by minimizing isolation procedures. This process, called GeneCalling, was validated by analysis of the gene expression profiles of normal and hypertrophic rat hearts following in vivo pressure overload.

Animals↗

PubMed1997

On the calculation of binding free energies using continuum methods: application to MHC class I protein-peptide interactions.

This paper describes a methodology to calculate the binding free energy (delta G) of a protein-ligand complex using a continuum model of the solvent. A formal thermodynamic cycle is used to decompose the binding free energy into electrostatic and non-electrostatic contributions. In this cycle, the reactants are discharged in water, associated as purely nonpolar entities, and the final complex is then recharged. The total electrostatic free energies of the protein, the ligand, and the complex in water are calculated with the finite difference Poisson-Boltzmann (FDPB) method. The nonpolar (hydrophobic) binding free energy is calculated using a free energy-surface area relationship, with a single alkane/water surface tension coefficient (gamma aw). The loss in backbone and side-chain configurational entropy upon binding is estimated and added to the electrostatic and the nonpolar components of delta G. The methodology is applied to the binding of the murine MHC class I protein H-2Kb with three distinct peptides, and to the human MHC class I protein HLA-A2 in complex with five different peptides. Despite significant differences in the amino acid sequences of the different peptides, the experimental binding free energy differences (delta delta Gexp) are quite small (< 0.3 and < 2.7 kcal/mol for the H-2Kb and HLA-A2 complexes, respectively). For each protein, the calculations are successful in reproducing a fairly small range of values for delta delta Gcalc (< 4.4 and < 5.2 kcal/mol, respectively) although the relative peptide binding affinities of H-2Kb and HLA-A2 are not reproduced. For all protein-peptide complexes that were treated, it was found that electrostatic interactions oppose binding whereas nonpolar interactions drive complex formation. The two types of interactions appear to be correlated in that larger nonpolar contributions to binding are generally opposed by increased electrostatic contributions favoring dissociation. The factors that drive the binding of peptides to MHC proteins are discussed in light of our results.

Animals↗

PubMed1993

Molecular dynamics study of the proton pump cycle of bacteriorhodopsin.

Retinal isomerization reactions, which are functionally important in the proton pump cycle of bacteriorhodopsin, were studied by molecular dynamics simulations performed on the complete protein. Retinal isomerizations were simulated in situ to account for the effects of the retinal-protein interactions. The protein structure employed was that described in Nonella et al. [Nonella, M., Windemuth, A., & Schulten, K. (1991) Photochem. Photobiol. 54, 937-948]. We investigated two mechanisms suggested previously for the proton pump cycle, the 13-cis isomerization model (C-T model) and the 13,14-dicis isomerization model. According to these models, retinal undergoes an all-trans-->13-cis or an all-trans-->13,14-dicis photoisomerization as the primary step of the pump cycle. From the simulations emerged a consistent picture of isomerization reactions and their control through the retinal-protein interactions which favors the 13,14-dicis isomerization model. Electrostatic interactions between the protonated Schiff base and its counterion are found to direct the stereochemistry of retinal in the photocycle: this and other interactions steer retinal toward the 13,14-dicis geometry in the primary photoreaction, toward the 13-cis geometry after its deprotonation, and to the all-trans isomeric form after its reprotonation. We also propose a catalytic mechanism involving hydrogen bonding of the Schiff base to main chain oxygen atoms of Val-49 and Thr-89 for the 13-cis-->all-trans thermal reisomerization of retinal. The all-trans-->13-cis primary photoreaction required by the "C-T" model was found to be inhibited by the Schiff base-counterion interaction, but the possibility of such a reaction can not be excluded. In order to investigate the "C-T" model, we enforced an all-trans-->13-cis photoisomerization in a simulation and monitored the subsequent protein conformational changes. The effects of internal water molecules on retinal isomerization reactions were studied by placing 16 water molecules in the proton conduction channel. The results indicate that water affects the nature of the Schiff base counterion and the nature of the primary photoreaction. Water chains, formed between positively and negatively charged protein groups in the proton conduction channel, are suggested to be involved in the reprotonation and deprotonation of retinal.

Bacteriorhodopsins↗

PubMed1992

Molecular dynamics simulation on a network of workstations using a machine-independent parallel programming language.

Molecular dynamics simulations investigate local and global motion in molecules. Several parallel computing approaches have been taken to attack the most computationally expensive phase of molecular simulations, the evaluation of long range interactions. This paper reviews these approaches and develops a straightforward but effective algorithm using the machine-independent parallel programming language, Linda. The algorithm was run both on a shared memory parallel computer and on a network of high performance Unix workstations. Performance benchmarks were performed on both systems using two proteins. This algorithm offers a portable cost-effective alternative for molecular dynamics simulations. In view of the increasing numbers of networked workstations, this approach could help make molecular dynamics simulations more easily accessible to the research community.

Algorithms↗

PubMed1991

Molecular dynamics simulation on a network of workstations using a machine-independent parallel programming language.

Molecular dynamics simulations investigate local and global motion in molecules. Several parallel computing approaches have been taken to attack the most computationally expensive phase of molecular simulations, the evaluation of long range interactions. This paper develops a straightforward but effective algorithm for molecular dynamics simulations using the machine-independent parallel programming language, Linda. The algorithm was run both on a shared memory parallel computer and on a network of high performance Unix workstations. Performance benchmarks were performed on both systems using two proteins. This algorithm offers a portable cost-effective alternative for molecular dynamics simulations. In view of the increasing numbers of networked workstations, this approach could help make molecular dynamics simulations more easily accessible to the research community.

Algorithms↗