David A Case

Rutgers, The State University of New Jersey, Нью-Брансуик, New Jersey, United States

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Publications (279)1415.09 Total impact

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    ABSTRACT: This manuscript presents the latest algorithmic and methodological developments to the structure-based design program DOCK 6.7 focused on an updated internal energy function, new anchor selection control, enhanced minimization options, a footprint similarity scoring function, a symmetry-corrected root-mean-square deviation algorithm, a database filter, and docking forensic tools. An important strategy during development involved use of three orthogonal metrics for assessment and validation: pose reproduction over a large database of 1043 protein-ligand complexes (SB2012 test set), cross-docking to 24 drug-target protein families, and database enrichment using large active and decoy datasets (Directory of Useful Decoys [DUD]-E test set) for five important proteins including HIV protease and IGF-1R. Relative to earlier versions, a key outcome of the work is a significant increase in pose reproduction success in going from DOCK 4.0.2 (51.4%) → 5.4 (65.2%) → 6.7 (73.3%) as a result of significant decreases in failure arising from both sampling 24.1% → 13.6% → 9.1% and scoring 24.4% → 21.1% → 17.5%. Companion cross-docking and enrichment studies with the new version highlight other strengths and remaining areas for improvement, especially for systems containing metal ions. The source code for DOCK 6.7 is available for download and free for academic users at http://dock.compbio.ucsf.edu/. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Journal of Computational Chemistry 06/2015; 36(15):1132-1156. DOI:10.1002/jcc.23905 · 3.60 Impact Factor
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    ABSTRACT: We present a unified, easily adaptable, open-source NMR exchange format (NEF) for NMR restraints and associated data. Developers of the major software packages for NMR structure determination and refinement have agreed to make their software able to read and write NEF-compliant files. Detailed specifications can be found at https://github.com/NMRExchangeFormat/NEF.
    Nature Structural & Molecular Biology 06/2015; 22(6):433-4. DOI:10.1038/nsmb.3041 · 13.31 Impact Factor
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    ABSTRACT: The 5' leader of the HIV-1 genome contains conserved elements that direct selective packaging of the unspliced, dimeric viral RNA into assembling particles. By using a (2)H-edited nuclear magnetic resonance (NMR) approach, we determined the structure of a 155-nucleotide region of the leader that is independently capable of directing packaging (core encapsidation signal; Ψ(CES)). The RNA adopts an unexpected tandem three-way junction structure, in which residues of the major splice donor and translation initiation sites are sequestered by long-range base pairing and guanosines essential for both packaging and high-affinity binding to the cognate Gag protein are exposed in helical junctions. The structure reveals how translation is attenuated, Gag binding promoted, and unspliced dimeric genomes selected, by the RNA conformer that directs packaging. Copyright © 2015, American Association for the Advancement of Science.
    Science 05/2015; 348(6237):917-921. DOI:10.1126/science.aaa9266 · 31.48 Impact Factor
  • David A Case
    Journal of biomolecular Structure & Dynamics 05/2015; 33(sup1):97. DOI:10.1080/07391102.2015.1032782 · 2.98 Impact Factor
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    ABSTRACT: Molecular dynamics simulations of crystals can enlighten interpretation of experimental x-ray crystallography data and elucidate structural dynamics and heterogeneity in biomolecular crystals. Furthermore, because of the direct comparison against experimental data, they can inform assessment of molecular dynamics methods and force fields. We present microsecond scale results for triclinic hen egg-white lysozyme in a supercell consisting of twelve independent unit cells using four contemporary force fields (Amber ff99SB, ff14ipq, ff14SB and CHARMM 36) in crystalline and solvated states (for ff14SB only). We find the crystal simulations consistent across multiple runs of the same force field and robust to various solvent equilibration schemes. However convergence is slow compared to solvent simulations. All of the tested force fields reproduce experimental structural and dynamic properties well, but Amber ff14SB maintains structure and reproduces fluctuations closest to the experimental model: its average backbone structure differs from the deposited structure by 0.37Å; by contrast, the average backbone structure in solution differs from the deposited by 0.65Å. All of the simulations are affected by a small progressive deterioration of the crystal lattice, presumably due to imperfect modeling of hydrogen bonding and other crystal contact interactions; this artifact is smallest in ff14SB, with average lattice positions deviating by 0.20Å from ideal. Side-chain disorder is surprisingly low with fewer than 30% of the non-glycine or alanine residues exhibiting significantly populated alternate rotamers. Our results provide helpful insight into the methodology of biomolecular crystal simulations and indicate directions for future work to obtain more accurate energy models for molecular dynamics. This article is protected by copyright. All rights reserved. © 2015 The Protein Society.
    Protein Science 05/2015; DOI:10.1002/pro.2713 · 2.85 Impact Factor
  • George M Giambaşu · Darrin M York · David A Case
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    ABSTRACT: RNA hairpins are widespread and very stable motifs that contribute decisively to RNA folding and biological function. The GTP1G2C3A4C5U6U7C8G9G10U11G12C13C14 construct (with a central UUCG tetraloop) has been extensively studied by solution NMR, and offers and excellent opportunity to evaluate the structure and dynamical description afforded by molecular dynamics (MD) simulations. Here, we compare average structural parameters and NMR relaxation rates estimated from a series of multiple independent explicit solvent MD simulations using the two most recent RNA AMBER force fields (ff99 and ff10). Predicted overall tumbling times are ∼20% faster than those inferred from analysis of NMR data and follow the same trend when temperature and ionic strength is varied. The Watson-Crick stem and the "canonical" UUCG loop structure is maintained in most simulations including the characteristic syn conformation along the glycosidic bond of G9, although some key hydrogen bonds in the loop are partially disrupted. Our analysis pinpoints G9-G10 backbone conformations as a locus of discrepancies between experiment and simulation. In general the results for the more recent force-field parameters (ff10) are closer to experiment than those for the older ones (ff99). This work provides a comprehensive and detailed comparison of state of the art MD simulations against a wide variety of solution NMR measurements. © 2015 Giambaşu et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.
    RNA 03/2015; 21(5). DOI:10.1261/rna.047357.114 · 4.62 Impact Factor
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    ABSTRACT: A new method is introduced to compute X-ray solution scattering profiles from atomic models of macromolecules. The three-dimensional version of the Reference Interaction Site Model (RISM) from liquid-state statistical mechanics is employed to compute the solvent distribution around the solute, including both water and ions. X-ray scattering profiles are computed from this distribution together with the solute geometry. We describe an efficient procedure for performing this calculation employing a Lebedev grid for the angular averaging. The intensity profiles (which involve no adjustable parameters) match experiment and molecular dynamics simulations up to wide angle for two proteins (lysozyme and myoglobin) in water, as well as the small-angle profiles for a dozen biomolecules taken from the BioIsis.net database. The RISM model is especially well-suited for studies of nucleic acids in salt solution. Use of fiber-diffraction models for the structure of duplex DNA in solution yields close agreement with the observed scattering profiles in both the small and wide angle scattering (SAXS and WAXS) regimes. In addition, computed profiles of anomalous SAXS signals (for Rb+ and Sr2+) emphasize the ionic contribution to scattering and are in reasonable agreement with experiment. In cases where an absolute calibration of the experimental data at q=0 is available, one can extract a count of the excess number of waters and ions; computed values depend on the closure that is assumed in the solution of the Ornstein-Zernike equations, with results from the Kovalenko-Hirata (KH) closure being closest to experiment for the cases studied here.
    The Journal of Chemical Physics 12/2014; 141(22). DOI:10.1063/1.4896220 · 3.12 Impact Factor
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    ABSTRACT: We present the ff14ipq force field, implementing the previously published IPolQ charge set for simulations of complete proteins. Minor modifications to the charge derivation scheme and van der Waals interactions between polar atoms are introduced. Torsion parameters are developed through a generational learning approach, based on gas-phase MP2/cc-pVTZ single-point energies computed of structures optimized by the force field itself rather than the quantum benchmark. In this manner, we sacrifice information about the true quantum minima in order to ensure that the force field maintains optimal agreement with the MP2/cc-pVTZ benchmark for the ensembles it will actually produce in simulations. A means of making the gas-phase torsion parameters compatible with solution-phase IPolQ charges is presented. The ff14ipq model is an alternative to ff99SB and other Amber force fields for protein simulations in programs that accommodate pair-specific Lennard-Jones combining rules. The force field gives strong performance on α-helical and β-sheet oligopeptides as well as globular proteins over microsecond time scale simulations, although it has not yet been tested in conjunction with lipid and nucleic acid models. We show how our choices in parameter development influence the resulting force field and how other choices that may have appeared reasonable would actually have led to poorer results. The tools we developed may also aid in the development of future fixed-charge and even polarizable biomolecular force fields.
    Journal of Chemical Theory and Computation 10/2014; 10(10):4515-4534. DOI:10.1021/ct500643c · 5.31 Impact Factor
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    ABSTRACT: We present the results of microsecond molecular dynamics simulations carried out by the ABC group of laboratories on a set of B-DNA oligomers containing the 136 distinct tetranucleotide base sequences. We demonstrate that the resulting trajectories have extensively sampled the conformational space accessible to B-DNA at room temperature. We confirm that base sequence effects depend strongly not only on the specific base pair step, but also on the specific base pairs that flank each step. Beyond sequence effects on average helical parameters and conformational fluctuations, we also identify tetranucleotide sequences that oscillate between several distinct conformational substates. By analyzing the conformation of the phosphodiester backbones, it is possible to understand for which sequences these substates will arise, and what impact they will have on specific helical parameters.
    Nucleic Acids Research 09/2014; 42(19). DOI:10.1093/nar/gku855 · 9.11 Impact Factor
  • Chunmei Liu · Pawel A Janowski · David A Case
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    ABSTRACT: Background: Molecular dynamics simulations can complement experimental measures of structure and dynamics of biomolecules. The quality of such simulations can be tested by comparisons to models refined against experimental crystallographic data. Methods: We report simulations of DNA and RNA duplexes in their crystalline environment. The calculations mimic the conditions for PDB entries 1D23 [d(CGATCGATCG)2] and 1RNA [(UUAUAUAUAUAUAA)2], and contain 8 unit cells, each with 4 copies of the Watson-Crick duplex: this yields in aggregate 64 mu s of duplex sampling for DNA and 16 mu s for RNA. Results: The duplex structures conform much more closely to the average structure seen in the crystal than do structures extracted from a solution simulation with the same force field. Sequence-dependent variations in helical parameters, and in groove widths, are largely maintained in the crystal structure, but are smoothed out in solution. However, the integrity of the crystal lattice is slowly degraded in both simulations, with the result that the interfaces between chains become heterogeneous. This problem is more severe for the DNA crystal, which has fewer inter-chain hydrogen bond contacts than does the RNA crystal. Conclusions: Crystal simulations using current force fields reproduce many features of observed crystal structures, but suffer from a gradual degradation of the integrity of the crystal lattice. General significance: The results offer insights into force-field simulations that test their ability to preserve weak interactions between chains, which will be of importance also in non-crystalline applications that involve binding and recognition. This article is part of a Special Issue entitled Recent developments of molecular dynamics.
    Biochimica et Biophysica Acta (BBA) - General Subjects 09/2014; 1850(5). DOI:10.1016/j.bbagen.2014.09.018 · 3.83 Impact Factor
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    ABSTRACT: The ionic atmosphere around nucleic acids remains only partially understood at atomic-level detail. Ion counting (IC) experiments provide a quantitative measure of the ionic atmosphere around nucleic acids and, as such, are a natural route for testing quantitative theoretical approaches. In this article, we replicate IC experiments involving duplex DNA in NaCl(aq) using molecular dynamics (MD) simulation, the three-dimensional reference interaction site model (3D-RISM), and nonlinear Poisson-Boltzmann (NLPB) calculations and test against recent buffer-equilibration atomic emission spectroscopy measurements. Further, we outline the statistical mechanical basis for interpreting IC experiments and clarify the use of specific concentration scales. Near physiological concentrations, MD simulation and 3D-RISM estimates are close to experimental results, but at higher concentrations (>0.7 M), both methods underestimate the number of condensed cations and overestimate the number of excluded anions. The effect of DNA charge on ion and water atmosphere extends 20-25 Å from its surface, yielding layered density profiles. Overall, ion distributions from 3D-RISMs are relatively close to those from corresponding MD simulations, but with less Na(+) binding in grooves and tighter binding to phosphates. NLPB calculations, on the other hand, systematically underestimate the number of condensed cations at almost all concentrations and yield nearly structureless ion distributions that are qualitatively distinct from those generated by both MD simulation and 3D-RISM. These results suggest that MD simulation and 3D-RISM may be further developed to provide quantitative insight into the characterization of the ion atmosphere around nucleic acids and their effect on structure and stability.
    Biophysical Journal 02/2014; 106(4):883-94. DOI:10.1016/j.bpj.2014.01.021 · 3.97 Impact Factor
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    Article: Amber 14
  • Article: Amber 14
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    ABSTRACT: We present a map-restrained self-guided Langevin dynamics (MapSGLD) simulation method for efficient targeted conformational search. The targeted conformational search represents simulations under restraints defined by experimental observations and/or by user specified structural requirements. Through map-restraints, this method provides an efficient way to maintain substructures and to set structure targets during conformational searching. With an enhanced conformational searching ability of self-guided Langevin dynamics, this approach is suitable for simulating large-scale conformational changes, such as the formation of macromolecular assemblies and transitions between different conformational states. Using several examples, we illustrate the application of this method in flexible fitting of atomic structures into density maps from cryo-electron microscopy.
    Journal of Structural Biology 07/2013; 183(3). DOI:10.1016/j.jsb.2013.07.006 · 3.23 Impact Factor
  • Biopolymers 07/2013; 99(12). DOI:10.1002/bip.22358 · 2.29 Impact Factor
  • Thomas E Cheatham · David A Case
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    ABSTRACT: We present a brief, and largely personal, history of computer simulations of DNA and RNA oligonucleotides, with an emphasis on duplex structures and the Amber force fields. Both explicit and implicit solvent models are described, and methods for estimating structures, thermodynamics and mechanical properties of duplexes are illustrated. This overview, covering about two decades of work, provides a perspective for a discussion of prospects and obstacles for future simulations of RNA and DNA. (c) 2013 Wiley Periodicals, Inc. Biopolymers 99: 969-977, 2013.
    Biopolymers 06/2013; 99(12). DOI:10.1002/bip.22331 · 2.29 Impact Factor
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    ABSTRACT: Molecular dynamics simulations of biomolecular crystals at atomic resolution have the potential to recover information on dynamics and heterogeneity hidden in the X-ray diffraction data. We present here 9.6 microseconds of dynamics in a small helical peptide crystal with 36 independent copies of the unit cell. The average simulation structure agrees with experiment to within 0.28 Å backbone and 0.42 Å all-atom rmsd; a model refined against the average simulation density agrees with the experimental structure to within 0.20 Å backbone and 0.33 Å all-atom rmsd. The R-factor between the experimental structure factors and those derived from this unrestrained simulation is 23% to 1.0 Å resolution. The B-factors for most heavy atoms agree well with experiment (Pearson correlation of 0.90), but B-factors obtained by refinement against the average simulation density underestimate the coordinate fluctuations in the underlying simulation where the simulation samples alternate conformations. A dynamic flow of water molecules through channels within the crystal lattice is observed, yet the average water density is in remarkable agreement with experiment. A minor population of unit cells is characterized by reduced water content, 310 helical propensity and a gauche(-) side-chain rotamer for one of the valine residues. Careful examination of the experimental data suggests that transitions of the helices are a simulation artifact, although there is indeed evidence for alternate valine conformeras and variable water content. This study highlights the potential for crystal simulations to detect dynamics and heterogeneity in experimental diffraction data, as well as to validate computational chemistry methods.
    Journal of the American Chemical Society 04/2013; 135(21). DOI:10.1021/ja401382y · 11.44 Impact Factor
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    ABSTRACT: Molecular dynamics (MD) allows the study of biological and chemical systems at the atomistic level on timescales from femtoseconds to milliseconds. It complements experiment while also offering a way to follow processes difficult to discern with experimental techniques. Numerous software packages exist for conducting MD simulations of which one of the widest used is termed Amber. Here, we outline the most recent developments, since version 9 was released in April 2006, of the Amber and AmberTools MD software packages, referred to here as simply the Amber package. The latest release represents six years of continued development, since version 9, by multiple research groups and the culmination of over 33 years of work beginning with the first version in 1979. The latest release of the Amber package, version 12 released in April 2012, includes a substantial number of important developments in both the scientific and computer science arenas. We present here a condensed vision of what Amber currently supports and where things are likely to head over the coming years. Figure 1 shows the performance in ns/day of the Amber package version 12 on a single-core AMD FX-8120 8-Core 3.6GHz CPU, the Cray XT5 system, and a single GPU GTX680. © 2012 John Wiley & Sons, Ltd.
    03/2013; 3(2). DOI:10.1002/wcms.1121
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    ABSTRACT: Azotobacter vinelandii nitrogenase Fe protein (Av2) provides a rare opportunity to investigate a [4Fe-4S] cluster at three oxidation levels in the same environment. Here, we report the structural and vibrational changes of this cluster upon reduction using a combination of NRVS and EXAFS spectroscopies with DFT calculations. Key to this work is the synergy between these three techniques as each generates highly complementary information and their analytical methodologies are interdependent. Importantly, the spectroscopic samples contained no glassing agents. NRVS and DFT reveal a systematic 10-30 cm-1 decrease in Fe-S stretching frequencies with each added electron. The "oxidized" [4Fe-4S]2+ state spectrum is consistent with and extends previous resonance Raman spectra. For the "reduced" [4Fe-4S]1+ state in Fe protein, and for any "all-ferrous" [4Fe-4S]0 cluster, these NRVS spectra are the first available vibrational data. NRVS simulations also allow estimation of the vibrational disorder for Fe-S and Fe-Fe distances, constraining the EXAFS analysis and allowing structural disorder to be estimated. For oxidized Av2, EXAFS and DFT indicate nearly equal Fe-Fe distances, while addition of one electron decreases the cluster symmetry. However, addition of the second electron to form the all-ferrous state induces significant structural change. EXAFS data recorded to k = 21 Å-1 indicates a 1:1 ratio of Fe-Fe interactions at 2.56 Å and 2.75 Å, a result consistent with DFT. Broken symmetry (BS) DFT rationalizes the interplay between redox state and the Fe-S and Fe-Fe distances as predominantly spin-dependent behavior inherent to the [4Fe-4S] cluster and perturbed by the Av2 protein environment.
    Journal of the American Chemical Society 02/2013; 135(7). DOI:10.1021/ja307027n · 11.44 Impact Factor
  • David A Case
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    ABSTRACT: NMR chemical shifts are sensitive probes of structure and dynamics in proteins. Empirical models, based on a large database of measured shifts, take an input structure and provide increasingly accurate estimates of the corresponding shifts. Quantum chemical calculations can provide the same information, with greater generality but (currently) with less accuracy. These methods are now providing new ways to approach NMR structure determination, and new insights into the conformational dynamics of proteins.
    Current Opinion in Structural Biology 02/2013; 23(2). DOI:10.1016/j.sbi.2013.01.007 · 8.75 Impact Factor

Publication Stats

34k Citations
1,415.09 Total Impact Points


  • 2009–2015
    • Rutgers, The State University of New Jersey
      • • Department of Chemical Biology
      • • BioMaPS Institute for Quantitative Biology
      Нью-Брансуик, New Jersey, United States
  • 2013
    • University of Utah
      • Department of Medicinal Chemistry
      Salt Lake City, Utah, United States
  • 1989–2009
    • The Scripps Research Institute
      • Department of Cell and Molecular Biology
      La Jolla, California, United States
  • 2005
    • Université de Picardie Jules Verne
      Amiens, Picardie, France
    • Novartis Institutes for BioMedical Research
      Cambridge, Massachusetts, United States
  • 2004
    • Brandeis University
      Волтам, Massachusetts, United States
  • 2003
    • Kitasato University
      • Department of Pharmaceutical Sciences
      Edo, Tōkyō, Japan
    • National Chung Hsing University
      • Department of Chemistry
      Taichung, Taiwan, Taiwan
  • 2001
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2000
    • University of California, San Diego
      • Department of Psychology
      San Diego, CA, United States
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
  • 1997
    • Torrey Pines Institute for Molecular Studies
      Port St. Lucie, Florida, United States
  • 1980–1989
    • University of California, Davis
      • Department of Chemistry
      Davis, California, United States
  • 1976–1979
    • Harvard University
      Cambridge, Massachusetts, United States