Showing papers by "David A. Case published in 1999"

Application of a pairwise generalized Born model to proteins and nucleic acids: inclusion of salt effects

Abstract: The Poisson–Boltzmann (PB) continuum solvent model shows considerable promise in providing a description of electrostatic solvation effects in biomolecules, but it can be computationally expensive to obtain converged results for large systems. Here we examine the performance of a pairwise generalized Born approximation (GB) method on multiple conformations of a small peptide, three proteins (protein A, myoglobin, and rusticyanin) and four RNA and DNA duplexes and hairpins containing 20–24 nucleotides. Charge and dielectric radii models were adapted from the CHARMM and Amber force fields. Finite difference PB calculations were carried out with the Delphi and PEP programs, and for several examples the matrix of all pairwise interaction energies was determined. In general, this parameterization of the GB model does an excellent job of reproducing the PB solvation energies for small molecules and for groups near the surface of larger molecules. There is a systematic tendency for this GB model to overestimate the effects of solvent screening (compared to PB) for pairs of buried atoms, but individual errors tend to cancel, and a good overall account of conformational energetics is obtained. A simple extension to the GB model to account for salt effects (in the linearized Debye–Huckel approximation) is proposed that does a good job of reproducing the salt dependence of the PB calculations. In many cases, it should be possible to replace PB calculations with much simpler GB models, but care needs to be taken for systems with extensive burial of charges or dipoles.

Calculations of NMR dipolar coupling strengths in model peptides.

Abstract: Ab initio MP2 and density functional quantum chemistry calculations are used to explore geometries and vibrational properties of N-methylacetamide and of the alanine dipeptide with backbone angles characteristic of helix and sheet regions in proteins. The results are used to explore one-bond direct dipolar couplings for the N–H, Cα–Hα, C′–N, and Cα–C′ bonds, as well as for the two-bond C′–H interaction. Vibrational averaging affects these dipolar couplings, and these effects can be expressed as effective bond lengths that are 0.5–3% larger than the true bond lengths; bending and torsion vibrations have a bigger influence on the effective coupling than do stretching vibrations. Because of zero-point motion, these effects are important even at low temperature. Hydrogen bonding interactions at the amide group also increase the N-H effective bond length. Although vibrational contributions to effective bond lengths are small, they can have a significant influence on the extraction of order parameters from relaxation data, and a knowledge of relative bond lengths is needed when several types of dipolar couplings are to be simultaneously used for refinement. The present computational results are compared to both solid- and liquid-state NMR experiments. The analysis suggests that secondary structural elements in many proteins may be more rigid than is commonly thought.

Base-rate training without case cues reduces base-rate neglect.

Abstract: Base-rate neglect is a persistent phenomenon in which subjects do not place sufficient weight on the probabilities of occurrence of relevant events. Two experiments with college students support the hypothesis that base-rate neglect may be minimized by providing base-rate training in the absence of case, or witness, cues, prior to introducing (or reintroducing) these cues. In Experiment 1, the hypothesis was supported by both within-subjects and between-groups assessments; in Experiment 2, the hypothesis was supported while the effects of instructions and a correction procedure were found to be minimal. In Experiment 1, but not in Experiment 2, training with case cues present also reduced base-rate neglect, but this effect was not sufficient to account for the effect of cue-absent base-rate training. Correction trials led some subjects to detect that the task contingencies were random; however, neither this nor actually telling subjects after the experiment that the task was indeed random led invariably to subjects’ describing the optimal strategy (which was to choose the richer alternative exclusively).