Ruth Huey

Scripps Research Institute

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Arthur J. Olson

Scripps Research Institute

David S. Goodsell

Scripps Research Institute

Garrett M. Morris

University of Oxford

Tony E. Hugli

Scripps Research Institute

Colin M. Bloor

University of California, San Diego

Michel F. Sanner

Scripps Research Institute

William E. Hart

University of Alabama

Michael E. Pique

Scripps Research Institute

W D Bowen

National Institutes of Health

Dennis R. Stewart

Molecular Medicine Research Institute

Cooperative Institutions

Scripps Research Institute

University of California, San Diego

Torrey Pines Institute For Molecular Studies

University of Naples Federico II

Brown University

Scripps Health

Scripps Clinic

University of North Carolina at Chapel Hill

Virginia Commonwealth University

Scripps Institution of Oceanography

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Papers

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Research Field

A semiempirical free energy force field with charge‐based desolvation

Journal of Computational Chemistry (2007)

Ruth Huey Garrett M. Morris Arthur J. Olson David S. Goodsell

Abstract The authors describe the development and testing of a semiempirical free energy force field for use in AutoDock4 and similar grid‐based docking methods. The force field is based on a comprehensive thermodynamic model that allows incorporation of intramolecular energies into the predicted free energy of binding. It also incorporates a charge‐based method for evaluation of desolvation designed to use a typical set of atom types. The method has been calibrated on a set of 188 diverse protein–ligand complexes of known structure and binding energy, and tested on a set of 100 complexes of ligands with retroviral proteases. The force field shows improvement in redocking simulations over the previous AutoDock3 force field. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2007

Force Field

Docking (animal)

10.1002/jcc.20634

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Citations (2,084)

Characterization of D-Ala2,Leu5,Cys6-enkephalin: a novel synthetic opioid peptide with slowed dissociation from delta receptors.

PubMed (1986)

W D Bowen Marianne V. Kelemen Ruth Huey Dennis R. Stewart

D-Ala2,Leu5,Cys6-enkephalin (DALCE) is a synthetic enkephalin analog which contains a reduced sulfhydryl group. It exhibited moderate delta selectivity (mu/delta IC50 ratio 13), but was not as selective as the disulfide-containing peptide, D-Pen2,5-enkephalin (DPDPE) (mu/delta ratio 1121). However, unlike other delta-selective peptides, DALCE exhibited a markedly slowed dissociation from receptors after pretreatment of membranes with micromolar concentrations. Pretreatment of membranes with 10 uM DALCE, followed by extensive washing, produced an 85-90% loss of 3H-DPDPE binding sites. D-Ala2,D-Leu5-enkephalin (DADLE), D-Ser2,Leu5,Thr6-enkephalin (DSTLE) and DPDPE produced losses of 59%, 70%, and 19%, respectively. The effect of DALCE was not reversed by a 60 min post-incubation in buffer containing 250 mM NaCl + 100 uM GMPPNP, a condition which produced nearly complete reversal of loss of sites by DADLE and DSTLE. DPDPE could be dissociated merely by post-incubation in TRIS-buffer alone for 15 min. The order for ease of dissociation after preincubation was DPDPE much greater than DADLE greater than DSTLE much greater than DALCE. The effect of DALCE was selective for delta sites, although higher concentrations of DALCE produced loss of mu sites. DALCE pretreatment had no effect on recovery of kappa sites. These results indicate that DALCE binds essentially irreversibly to delta receptors.

DADLE

δ-opioid receptor

Dissociation constant

Source

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AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility

Journal of Computational Chemistry (2009)

Garrett M. Morris Ruth Huey William Lindstrom Michel F. Sanner Richard K. Belew

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. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009

Docking (animal)

Protein–ligand docking

Graphical user interface

10.1002/jcc.21256

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Citations (20,412)

Characterization of a C5a receptor on human polymorphonuclear leukocytes (PMN).

The Journal of Immunology (1985)

Ruth Huey Tony E. Hugli

Elucidation of the interactions between C5a and granulocytes is central to understanding the role of C5a in inflammation. In this study, interactions between C5a and PMN have been studied at two levels. Binding of human C5a to intact human cells has been characterized by using the radiolabeled ligand 125I-C5a. Binding is shown to be reversible, saturable, and to reach equilibrium in 60 to 90 min at 0 degrees C. Results show high affinity C5a binding sites with Kd = 2 X 10(-9) M and a range of 50,000 to 113,000 binding sites per PMN. These values for C5a receptors are comparable with the number of fMLP and LTB4 receptors on PMN. Binding of C5a to PMN fails to reach equilibrium at 37 degrees C because there is an irreversible loss of available surface receptors caused by an active internalization of the ligand-receptor complex. Interactions between C5a and human PMN were characterized further by cross-linking experiments, with the use of ethylene glycol bis succinimidylsuccinate (EGS). Cross-linking of 125I-C5a to intact PMN followed by subcellular fractionation revealed a single radioactive band present only in the plasma membrane fraction and visualized by autoradiography. Similar experiments resulted in a covalent linkage between 125I-C5a and a component in the isolated plasma membrane of PMN. The covalent complex containing C5a and a putative receptor has been visualized by autoradiography as a single 60,000 Mr complex on SDS-PAGE. The complex is not present when experiments are performed in the presence of excess unlabeled C5a or in the absence of EGS. Therefore, the putative receptor for C5a on human neutrophils is estimated to be approximately 48,000 Mr, assuming contribution of 12,000 to 13,000 daltons by the ligand 125I-C5a.

C5a receptor

10.4049/jimmunol.135.3.2063

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Citations (109)

Contraction of guinea pig lung by synthetic oligopeptides related to human C3a

Immunopharmacology (1984)

Ruth Huey Bruce W. Erickson Colin M. Bloor Tony E. Hugli

Anaphylatoxin

Pentapeptide repeat

Tachyphylaxis

10.1016/0162-3109(84)90055-9

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Citations (16)

Functional Proteomic and Structural Insights into Molecular Recognition in the Nitrilase Family Enzymes

Biochemistry (2008)

Katherine T. Barglow Kumar Singh Saikatendu Michael H. Bracey Ruth Huey Garrett M. Morris

Nitrilases are a large and diverse family of nonpeptidic C−N hydrolases. The mammalian genome encodes eight nitrilase enzymes, several of which remain poorly characterized. Prominent among these are nitrilase-1 (Nit1) and nitrilase-2 (Nit2), which, despite having been shown to exert effects on cell growth and possibly serving as tumor suppressor genes, are without known substrates or selective inhibitors. In previous studies, we identified several nitrilases, including Nit1 and Nit2, as targets for dipeptide−chloroacetamide activity-based proteomics probes. Here, we have used these probes, in combination with high-resolution crystallography and molecular modeling, to systematically map the active site of Nit2 and identify residues involved in molecular recognition. We report the 1.4 Å crystal structure of mouse Nit2 and use this structure to identify residues that discriminate probe labeling between the Nit1 and Nit2 enzymes. Interestingly, some of these residues are conserved across all vertebrate Nit2 enzymes and, conversely, not found in any vertebrate Nit1 enzymes, suggesting that they are key discriminators of molecular recognition between these otherwise highly homologous enzymes. Our findings thus point to a limited set of active site residues that establish distinct patterns of molecular recognition among nitrilases and provide chemical probes to selectively perturb the function of these enzymes in biological systems.

Nitrilase

10.1021/bi801786y

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Citations (52)

Using AutoDock for Ligand‐Receptor Docking

Current Protocols in Bioinformatics (2008)

Garrett M. Morris Ruth Huey Arthur J. Olson

Abstract This unit describes how to set up and analyze ligand‐protein docking calculations using AutoDock and the graphical user interface, AutoDockTools (ADT). The AutoDock scoring function is a subset of the AMBER force field that treats molecules using the United Atom model. The unit uses an X‐ray crystal structure of Indinavir bound to HIV‐1 protease taken from the Protein Data Bank ( UNIT 1.9 ) and shows how to prepare the ligand and receptor for AutoGrid, which computes grid maps needed by AutoDock. Indinavir is prepared for AutoDock, adding the polar hydrogens, and partial charges, and defining the rotatable bonds that will be explored during the docking. The input files for AutoGrid and AutoDock are created, and then the grid map calculation run, followed by the docking calculation in AutoDock. Finally, this unit describes some of the ways the results can be analyzed using AutoDockTools. Curr. Protoc. Bioinform . 24:8.14.1‐8.14.40. © 2008 by John Wiley & Sons, Inc.

AutoDock

Docking (animal)

Protein–ligand docking

Indinavir

10.1002/0471250953.bi0814s24

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Citations (954)

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

Journal of Computational Chemistry (1998)

Garrett M. Morris David S. Goodsell Robert S. Halliday Ruth Huey William E. Hart

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 error of 9.11 kJ mol−1 (2.177 kcal mol−1) and was chosen as the new energy function. The new search methods and empirical free energy function are available in AUTODOCK, version 3.0. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1639–1662, 1998

AutoDock

Docking (animal)

10.1002/(sici)1096-987x(19981115)19:14<1639::aid-jcc10>3.0.co;2-b

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Citations (10,337)

C5a receptor

Methods in enzymology on CD-ROM/Methods in enzymology (1987)

Ruth Huey Tony E. Hugli

C5a receptor

Cell surface receptor

10.1016/0076-6879(87)50112-4

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