Irwin D. Kuntz

Bio: Irwin D. Kuntz is an academic researcher from University of California, San Francisco. The author has contributed to research in topics: Docking (molecular) & Protein structure. The author has an hindex of 78, co-authored 236 publications receiving 26163 citations. Previous affiliations of Irwin D. Kuntz include St. Jude Children's Research Hospital & Princeton University.

DOCK 4.0: Search strategies for automated molecular docking of flexible molecule databases

Abstract: In this paper we describe the search strategies developed for docking flexible molecules to macomolecular sites that are incorporated into the widely distributed DOCK software, version 40 The search strategies include incremental construction and random conformation search and utilize the existing Coulombic and Lennard-Jones grid-based scoring function The incremental construction strategy is tested with a panel of 15 crystallographic testcases, created from 12 unique complexes whose ligands vary in size and flexibility For all testcases, at least one docked position is generated within 2 A of the crystallographic position For 7 of 15 testcases, the top scoring position is also within 2 A of the crystallographic position The algorithm is fast enough to successfully dock a few testcases within seconds and most within 100 s The incremental construction and the random search strategy are evaluated as database docking techniques with a database of 51 molecules docked to two of the crystallographic testcases Incremental construction outperforms random search and is fast enough to reliably rank the database of compounds within 15 s per molecule on an SGI R10000 cpu

Hydration of Proteins and Polypeptides

Abstract: Publisher Summary This chapter describes many of the techniques employed to study water–macromolecules interactions, their general usefulness, points out areas of mutual support and contradiction. The chapter also presents hydration of other macromolecules and the hydration of small molecules. Four broadly based approaches to operational definitions of hydration include—(1) preferential hydration, (2) hydrodynamic hydration, (3) structural hydration, and (4) low temperature hydration. The use of high resolution X-ray and neutron diffraction data on protein crystals provides an independent approach for estimation of hydration. The chapter presents several proposals for predicting protein hydration based on the amino acid composition of the protein; however, the two main questions concerned include—whether ionic groups are more hydrated than other polar groups, and whether the amide and peptide functions are hydrated or not. Low pH, and to a much smaller degree, high pH should dehydrate proteins. Intermolecular association via ionic mechanisms should be strongly dehydrating; whereas hydrophobic interactions should not have much effect on hydration levels. Although, there is a presumption that both the enthalpy and the entropy are negative for the process of adding water molecules to isolated proteins, which are maintained in their native conformations, but there is no unequivocal evidence for this.

Structure-based strategies for drug design and discovery.

Abstract: Most drugs have been discovered in random screens or by exploiting information about macromolecular receptors One source of this information is in the structures of critical proteins and nucleic acids The structure-based approach to design couples this information with specialized computer programs to propose novel enzyme inhibitors and other therapeutic agents Iterated design cycles have produced compounds now in clinical trials The combination of molecular structure determination and computation is emerging as an important tool for drug development These ideas will be applied to acquired immunodeficiency syndrome (AIDS) and bacterial drug resistance

Automated docking with grid-based energy evaluation

Abstract: The ability to generate feasible binding orientations of a small molecule within a site of known structure is important for ligand design. We present a method that combines a rapid, geometric docking algorithm with the evaluation of molecular mechanics interaction energies. The computational costs of evaluation are minimal because we precalculate the receptor-dependent terms in the potential function at points on a three-dimensional grid. In four test cases where the components of crystallographically determined complexes are redocked, the «force field» score correctly identifies the family of orientations closest to the experimental binding geometry

UCSF Chimera--a visualization system for exploratory research and analysis.

Abstract: The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility

Abstract: We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique.

All-atom empirical potential for molecular modeling and dynamics studies of proteins.

Abstract: New protein parameters are reported for the all-atom empirical energy function in the CHARMM program. The parameter evaluation was based on a self-consistent approach designed to achieve a balance between the internal (bonding) and interaction (nonbonding) terms of the force field and among the solvent−solvent, solvent−solute, and solute−solute interactions. Optimization of the internal parameters used experimental gas-phase geometries, vibrational spectra, and torsional energy surfaces supplemented with ab initio results. The peptide backbone bonding parameters were optimized with respect to data for N-methylacetamide and the alanine dipeptide. The interaction parameters, particularly the atomic charges, were determined by fitting ab initio interaction energies and geometries of complexes between water and model compounds that represented the backbone and the various side chains. In addition, dipole moments, experimental heats and free energies of vaporization, solvation and sublimation, molecular volume...

Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function

Abstract: A novel and robust automated docking method that predicts the bound conformations of flexible ligands to macromolecular targets has been developed and tested, in combination with a new scoring function that estimates the free energy change upon binding. Interestingly, this method applies a Lamarckian model of genetics, in which environmental adaptations of an individual's phenotype are reverse transcribed into its genotype and become . heritable traits sic . We consider three search methods, Monte Carlo simulated annealing, a traditional genetic algorithm, and the Lamarckian genetic algorithm, and compare their performance in dockings of seven protein)ligand test systems having known three-dimensional structure. We show that both the traditional and Lamarckian genetic algorithms can handle ligands with more degrees of freedom than the simulated annealing method used in earlier versions of AUTODOCK, and that the Lamarckian genetic algorithm is the most efficient, reliable, and successful of the three. The empirical free energy function was calibrated using a set of 30 structurally known protein)ligand complexes with experimentally determined binding constants. Linear regression analysis of the observed binding constants in terms of a wide variety of structure-derived molecular properties was performed. The final model had a residual standard y1 y1 .