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Author (up) Parsons, A.B.; Brost, R.L.; Ding, H.; Li, Z.; Zhang, C.; Sheikh, B.; Brown, G.W.; Kane, P.M.; Hughes, T.R.; Boone, C. file  url
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  Title Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways Type Journal Article
  Year 2004 Publication Nature Biotechnology Abbreviated Journal Nat Biotechnol  
  Volume 22 Issue 1 Pages 62-69  
  Keywords Biotechnology/*methods; Cluster Analysis; Drug Industry/*methods; *Drug Resistance; Fungal Proteins/metabolism; Gene Deletion; *Gene Expression Regulation; Mutation; Pharmacogenetics; Proton-Translocating ATPases/metabolism; Saccharomyces cerevisiae/*genetics; Software  
  Abstract Bioactive compounds can be valuable research tools and drug leads, but it is often difficult to identify their mechanism of action or cellular target. Here we investigate the potential for integration of chemical-genetic and genetic interaction data to reveal information about the pathways and targets of inhibitory compounds. Taking advantage of the existing complete set of yeast haploid deletion mutants, we generated drug-hypersensitivity (chemical-genetic) profiles for 12 compounds. In addition to a set of compound-specific interactions, the chemical-genetic profiles identified a large group of genes required for multidrug resistance. In particular, yeast mutants lacking a functional vacuolar H(+)-ATPase show multidrug sensitivity, a phenomenon that may be conserved in mammalian cells. By filtering chemical-genetic profiles for the multidrug-resistant genes and then clustering the compound-specific profiles with a compendium of large-scale genetic interaction profiles, we were able to identify target pathways or proteins. This method thus provides a powerful means for inferring mechanism of action.  
  Call Number Serial 339  
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Author (up) Phillips, J.C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R.D.; Kale, L.; Schulten, K. file  url
doi  openurl
  Title Scalable molecular dynamics with NAMD Type Journal Article
  Year 2005 Publication Journal of Computational Chemistry Abbreviated Journal J Comput Chem  
  Volume 26 Issue 16 Pages 1781-1802  
  Keywords Algorithms; Aquaporins/chemistry; Cell Membrane/chemistry; *Computer Simulation; Glycophorin/chemistry; *Models, Biological; *Models, Chemical; Models, Molecular; Repressor Proteins/chemistry; *Software; Software Design; Static Electricity; Ubiquitin/chemistry  
  Abstract NAMD is a parallel molecular dynamics code designed for high-performance simulation of large biomolecular systems. NAMD scales to hundreds of processors on high-end parallel platforms, as well as tens of processors on low-cost commodity clusters, and also runs on individual desktop and laptop computers. NAMD works with AMBER and CHARMM potential functions, parameters, and file formats. This article, directed to novices as well as experts, first introduces concepts and methods used in the NAMD program, describing the classical molecular dynamics force field, equations of motion, and integration methods along with the efficient electrostatics evaluation algorithms employed and temperature and pressure controls used. Features for steering the simulation across barriers and for calculating both alchemical and conformational free energy differences are presented. The motivations for and a roadmap to the internal design of NAMD, implemented in C++ and based on Charm++ parallel objects, are outlined. The factors affecting the serial and parallel performance of a simulation are discussed. Finally, typical NAMD use is illustrated with representative applications to a small, a medium, and a large biomolecular system, highlighting particular features of NAMD, for example, the Tcl scripting language. The article also provides a list of the key features of NAMD and discusses the benefits of combining NAMD with the molecular graphics/sequence analysis software VMD and the grid computing/collaboratory software BioCoRE. NAMD is distributed free of charge with source code at www.ks.uiuc.edu.  
  Call Number Serial 418  
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Author (up) Podlich, D.W.; Cooper, M. file  url
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  Title QU-GENE: a simulation platform for quantitative analysis of genetic models Type Journal Article
  Year 1998 Publication Bioinformatics (Oxford, England) Abbreviated Journal Bioinformatics  
  Volume 14 Issue 7 Pages 632-653  
  Keywords Computer Simulation; Epistasis, Genetic; Genotype; Models, Genetic; Software  
  Abstract MOTIVATION: Classical quantitative genetics theory makes a number of simplifying assumptions in order to develop mathematical expressions that describe the mean and variation (genetic and phenotypic) within and among populations, and to predict how these are expected to change under the influence of external forces. These assumptions are often necessary to render the development of many aspects of the theory mathematically tractable. The availability of high-speed computers today provides opportunity for the use of computer simulation methodology to investigate the implications of relaxing many of the assumptions that are commonly made. RESULTS: QU-GENE (QUantitative-GENEtics) was developed as a flexible computer simulation platform for the quantitative analysis of genetic models. Three features of the QU-GENE software that contribute to its flexibility are (i) the core E(N:K) genetic model, where E is the number of types of environment, N is the number of genes, K indicates the level of epistasis and the parentheses indicate that different N:K genetic models can be nested within types of environments, (ii) the use of a two-stage architecture that separates the definition of the genetic model and genotype-environment system from the detail of the individual simulation experiments and (iii) the use of a series of interactive graphical windows that monitor the progress of the simulation experiments. The E(N:K) framework enables the generation of families of genetic models that incorporate the effects of genotype-by-environment (G x E) interactions and epistasis. By the design of appropriate application modules, many different simulation experiments can be conducted for any genotype-environment system. The structure of the QU-GENE simulation software is explained and demonstrated by way of two examples. The first concentrates on some aspects of the influence of G x E interactions on response to selection in plant breeding, and the second considers the influence of multiple-peak epistasis on the evolution of a four-gene epistatic network.  
  Call Number Serial 19  
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