Richard S. Judson

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 individuals 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.

The application of time-dependent wavepacket methods to reactive scattering

In this article, we review several methods for performing numerically-exact reactive scattering calculations using time-dependent wavepackets. The basic idea we imply is to take the multi-arrangement reactive problem and reformulate it as one or more inelastic ones. In the simplest method, we extract total reaction probabilities by calculating the flux of the wavepacket as it leaves the interaction region in the direction of the reactive arrangement. To make this practical, we use complex potentials that absorb the wavepacket before it reaches the numerical grid boundary. We describe methods that generate observables ranging from total, energy-averaged reaction probabilities up to energy- and state-resolved S-matrix elements. We also review techniques for efficiently performing the necessary inelastic wavepacket propagation.

How many SNPs does a genome-wide haplotype map require?

We derive and compare several estimates of the number of SNPs that would be required to form the basis of a complete haplotype survey of the human genome. Our estimates make use of reports published by Stephens et al. [1], Patil et al. [2] and Daly et al. [3]. The estimated number of SNPs required for a genome-wide haplotype survey ranges from 180K (based on a European sample of 16 chromosomes) to 600K (based on an ethnically diverse sample of 164 chromosomes). We discuss the implications of using cohorts of different size and ethnic composition and the usefulness of public SNP databases for this effort. Finally, we estimate the experimental effort and cost required to complete a genome-wide haplotype survey.

Analysis of the genetic algorithm method of molecular conformation determination

Many important problems in chemistry require knowledge of the 3‐D conformation of a molecule. A commonly used computational approach is to search for a variety of low‐energy conformations. Here, we study the behavior of the genetic algorithm (GA) method as a global search technique for finding these low‐energy conformations. Our test molecule is cyclic hexaglycine. The goal of this study is to determine how to best utilize GAs to find low‐energy populations of conformations given a fixed amount of CPU time. Two measures are presented that help monitor the improvement in the GA populations and their loss of diversity. Different hybrid methods that combine coarse GA global search with local gradient minimization are evaluated. We present several specific recommendations about trade‐offs when choosing GA parameters such as population size, number of generations, rate of interaction between subpopulations, and combinations of GA and gradient minimization. In particular, our results illustrate why approaches that emphasize convergence of the GA can actually decrease its effectiveness as a global conformation search method.

Conformational searching methods for small molecules II: genetic algorithm approach

We demonstrate the use of a genetic algorithm (GA) search procedure for finding low‐energy conformations of small to medium organic molecules (1–12 rotatable bonds). GAS are in a class of biologically motivated optimization methods that evolve a population of individuals where individuals who are more “fit” have a higher probability of surviving into subsequent generations. Here, an individual is a conformation of a given molecule and the fitness is the molecules conformational energy. In the course of a simulated evolution, the population produces conformations having increasingly lower energy. We test the GA method on a suite of 72 molecules and compare the performance against the CSEARCH algorithm in Sybyl. For molecules with more than eight rotatable bonds, the GA method is more efficient computationally and as the number of rotatable bonds increases the relative efficiency of the GA method grows. The GA method also found energies equal to or lower than the energy of the relaxed crystal structure in the large majority of cases.

Notes from the SNP vs. haplotype front

Single nucleotide polymorphisms (SNPs) and haplotypes are commonly used genetic markers in clinical studies. We provide some broad guidelines for deciding which of the two is most appropriate in particular circumstances. Molecular haplotyping techniques are also briefly reviewed and contrasted with electronic approaches.

Total integral reactive cross sections for F + H2 → HF + H: comparison of converged quantum, quasiclassical trajectory and experimental results

Abstract We report converged quantum total integral reactive cross sections for the reaction F + H 2 → HF + H, for initial rotational states j i = 0 and 1, using a time-dependent method. Our results are compared to classical results and to the experimental results of Neumark . Strong quantum effects are found in the threshold region for both initial states; i.e. in the dependence of the reaction on initial state for low energies. The classical results agree better with experiment than do the quantum results; this appears to be due to errors in the potential used.

A comparison of a direct search method and a genetic algorithm for conformational searching

We present results from the application of two conformational searching methods: genetic algorithms (GA) and direct search methods for finding low energy conformations of organic molecules. GAs are in a class of biologically motivated optimization methods that evolve a population of individuals in which individuals who are more “fit” have a higher probability of surviving into subsequent generations. The parallel direct search method (PDS) is a type of pattern search method that uses an adaptive grid to search for minima. Both methods found energies equal to or lower than the energy of the relaxed crystal structure in all cases, at a relatively small cost in CPU time. We suggest that either method would be a good candidate to find 3‐D conformations in a large scale screening application.

Docking flexible molecules: A case study of three proteins

A genetic algorithm (GA) conformation search method is used to dock a series of flexible molecules into one of three proteins. The proteins examined are thermolysin (tmn), carboxypeptidase A (cpa), and dihydrofolate reductase (dfr). In the latter two proteins, the crystal ligand was redocked. For thermolysin, we docked eight ligands into a protein conformation derived from a single crystal structure. The bound conformations of the other ligands in tmn are known. In the cpa and dfr cases, and in seven of the eight tmn ligands, the GA docking method found conformations within 1.6 Å root mean square (rms) of the relaxed crystal conformation.

A genetic algorithm based method for docking flexible molecules

Abstract We describe a computational method for docking flexible molecules into protein binding sites. The method uses a genetic algorithm (GA) to search the combined conformation/orientation space of the molecule to find low energy conformations. Several techniques are described that increase the efficiency of the basic search method. These include the use of several interacting GA subpopulations or niches; the use of a “growing” algorithm that initially docks only a small part of the molecule, and the use of gradient minimization during the search. To illustrate the method, we dock Cbz-GlyP-Leu-Leu (ZGLL) into thermolysin. This system was chosen because a well refined crystal structure is available and because another docking method had previously been tested on this system. Our method is able to find conformations that lie physically close to and in some cases lower in energy than the crystal conformation in reasonable periods of time on readily available hardware.