Parallelization of the discrete gradient method of non-smooth optimization and its applications

We investigate parallelization and performance of the discrete gradient method of nonsmooth optimization. This derivative free method is shown to be an effective optimization tool, able to skip many shallow local minima of nonconvex nondifferentiable objective functions. Although this is a sequential iterative method, we were able to parallelize critical steps of the algorithm, and this lead to a significant improvement in performance on multiprocessor computer clusters. We applied this method to a difficult polyatomic clusters problem in computational chemistry, and found this method to outperform other algorithms. <br /

Statistical and energetic analysis of side-chain conformations in oligopeptides.

The distributions of side-chain conformations in 258 crystal structures of oligopeptides have been analyzed. The sample contains 321 residues having side chains that extend beyond the C beta atom. Statistically observed preferences of side-chain dihedral angles are summarized and correlated with stereochemical and energetic constraints. The distributions are compared with observed distributions in proteins of known X-ray structures and with computed minimum-energy conformations of amino acid derivatives. The distributions are similar in all three sets of data, and they appear to be governed primarily by intraresidue interactions. In side chains with no beta-branching, the most important interactions that determine chi 1 are those between the C gamma H2 group and atoms of the neighboring peptide groups. As a result, the g- conformation (chi 1 congruent to -60 degrees) occurs most frequently for rotation around the C alpha-C beta bond in oligopeptides, followed by the t conformation (chi 1 congruent to 180 degrees), while the g+ conformation (chi 1 congruent to 60 degrees) is least favored. In residues with beta-branching, steric repulsions between the C gamma H2 or C gamma H3 groups and backbone atoms govern the distribution of chi 1. The extended (t) conformation is highly favored for rotation around the C beta-C gamma and C gamma-C delta bonds in unbranched side chains, because the t conformer has a lower energy than the g+ and g- conformers in hydrocarbon chains. This study of the observed side-chain conformations has led to a refinement of one of the energy parameters used in empirical conformational energy computations

Intramolecular versus intermolecular disulfide bonds in prion proteins.

Prion protein (PrP) is the major component of the partially protease-resistant aggregate that accumulates in mammals with transmissible spongiform encephalopathies. The two cysteines of the scrapie form, PrP(Sc), were found to be in their oxidized (i.e. disulfide) form (Turk, E., Teplow, D. B., Hood, L. E., and Prusiner, S. B. (1988) Eur. J. Biochem. 176, 21-30); however, uncertainty remains as to whether the disulfide bonds are intra- or intermolecular. It is demonstrated here that the monomers of PrP(Sc) are not linked by intermolecular disulfide bonds. Furthermore, evidence is provided that PrP(Sc) can induce the conversion of the oxidized, disulfide-intact form of the monomeric cellular prion protein to its protease-resistant form without the temporary breakage and subsequent re-formation of the disulfide bonds in cell-free reactions

Tetra Detector Analysis of Membrane Proteins

Well-characterized membrane protein detergent complexes (PDC) that are pure, homogenous and stable with minimized excess detergent micelles are essential for functional assays and crystallization studies. Procedural steps to measure the mass, size, shape, homogeneity and molecular composition of PDCs and their host detergent micelle using size exclusion chromatography (SEC) with a Viscotek tetra detector array (TDA; absorbance, refractive index, light scattering and viscosity detectors) are presented. The value of starting with a quality PDC sample, the precision and accuracy of the results, and the use of a digital bench top refractometer are emphasized. An alternate and simplified purification and characterization approach using SEC with dual absorbance and refractive index detectors to optimize detergent and lipid concentration while measuring the PDC homogeneity are also described. Applications relative to purification and characterization goals are illustrated as well