David A Case

Rutgers, The State University of New Jersey, New Brunswick, New Jersey, United States

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Publications (242)1141.81 Total impact

  • [Show abstract] [Hide abstract]
    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). · 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. · 5.31 Impact Factor
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    ABSTRACT: We present the results of microsecond molecular dy-namics 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 ex-tensively sampled the conformational space acces-sible 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 conforma-tional fluctuations, we also identify tetranucleotide sequences that oscillate between several distinct conformational substates. By analyzing the confor-mation of the phosphodiester backbones, it is pos-sible to understand for which sequences these sub-states will arise, and what impact they will have on specific helical parameters.
    Nucleic Acids Research 09/2014; · 8.81 Impact Factor
  • Chunmei Liu, Pawel A Janowski, David A Case
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    ABSTRACT: 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.
    Biochimica et Biophysica Acta (BBA) - General Subjects 09/2014; · 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. · 3.83 Impact Factor
  • Article: Amber 14
  • Article: Amber 14
  • Biopolymers 07/2013; · 2.29 Impact Factor
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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; · 3.37 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.
    Biopolymers 06/2013; · 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; · 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.
    Wiley Interdisciplinary Reviews: Computational Molecular Science. 03/2013; 3(2).
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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; · 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; · 8.75 Impact Factor
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    ABSTRACT: We have developed the IPolQ method for fitting non-polarizable point charges to implicitly represent the energy of polarization for systems in pure water. The method involves iterative cycles of molecular dynamics simulations to estimate the water charge density around the solute of interest followed by quantum mechanical calculations at the MP2/cc-pV(T+d)Z level to determine updated solute charges. Lennard-Jones parameters are updated starting from the Amber FF99SB nonbonded parameter set to accommodate the new charge model, guided by the comparisons to experimental hydration free energies (HFEs) of neutral amino acid side chain analogs and assumptions about the computed HFEs for charged side chains. These Lennard-Jones parameter adjustments for side chain analogs are assumed to be transferable to amino acids generally, and new charges for all standard amino acids are then derived in the presence of water modeled by TIP4P-Ew. Overall, the new charges depict substantially more polarized amino acids, particularly in the backbone moieties, than previous Amber charge sets. Efforts to complete a new force field with appropriate torsion parameters for this charge model are underway. The IPolQ method is general, applicable to arbitrary solutes.
    The Journal of Physical Chemistry B 02/2013; · 3.38 Impact Factor
  • In Suk Joung, Tyler Luchko, David A Case
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    ABSTRACT: Using the dielectrically consistent reference interaction site model (DRISM) of molecular solvation, we have calculated structural and thermodynamic information of alkali-halide salts in aqueous solution, as a function of salt concentration. The impact of varying the closure relation used with DRISM is investigated using the partial series expansion of order-n (PSE-n) family of closures, which includes the commonly used hypernetted-chain equation (HNC) and Kovalenko-Hirata closures. Results are compared to explicit molecular dynamics (MD) simulations, using the same force fields, and to experiment. The mean activity coefficients of ions predicted by DRISM agree well with experimental values at concentrations below 0.5 m, especially when using the HNC closure. As individual ion activities (and the corresponding solvation free energies) are not known from experiment, only DRISM and MD results are directly compared and found to have reasonably good agreement. The activity of water directly estimated from DRISM is nearly consistent with values derived from the DRISM ion activities and the Gibbs-Duhem equation, but the changes in the computed pressure as a function of salt concentration dominate these comparisons. Good agreement with experiment is obtained if these pressure changes are ignored. Radial distribution functions of NaCl solution at three concentrations were compared between DRISM and MD simulations. DRISM shows comparable water distribution around the cation, but water structures around the anion deviate from the MD results; this may also be related to the high pressure of the system. Despite some problems, DRISM-PSE-n is an effective tool for investigating thermodynamic properties of simple electrolytes.
    The Journal of Chemical Physics 01/2013; 138(4):044103. · 3.12 Impact Factor
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    ABSTRACT: We report AMBER force field parameters for biological simulations involving phosphorylation of serine, threonine or tyrosine. The initial parameters used RESP fitting for the atomic partial charges and standard values for all other parameters such as Lennard-Jones coefficients. These were refined with the aid of a thermodynamic cycle consisting of experimentally determined pKa values, solvation energies from molecular dynamics free energy simulations, and gas phase basicities from QM calculations. A polarization energy term was included to account for the charge density change between the gas-phase and solution, and solvation free energies were determined using thermodynamic integration. Parameter adjustment is required to obtain consistent thermodynamic results with better balanced electrostatic interactions between water and the phosphate oxygens. To achieve this we modified the phosphate oxygen radii. A thermodynamically consistent parameter set can be derived for monoanions and requires an increase of the van der Waals phosphate oxygen radii of approximately 0.09 Å. Larger, residue-specific radii appear to be needed for dianions. The revised parameters developed here should be of particular interest for environments where simulations of multiple protonation states may be of interest.
    Journal of Chemical Theory and Computation 11/2012; 8(11):4405-4412. · 5.31 Impact Factor
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    ABSTRACT: In conjunction with the recent American Chemical Society symposium titled "Docking and Scoring: A Review of Docking Programs" the performance of the DOCK6 program was evaluated through (1) pose reproduction and (2) database enrichment calculations on a common set of organizer-specified systems and datasets (ASTEX, DUD, WOMBAT). Representative baseline grid score results averaged over five docking runs yield a relatively high pose identification success rate of 72.5 % (symmetry corrected rmsd) and sampling rate of 91.9 % for the multi site ASTEX set (N = 147) using organizer-supplied structures. Numerous additional docking experiments showed that ligand starting conditions, symmetry, multiple binding sites, clustering, and receptor preparation protocols all affect success. Encouragingly, in some cases, use of more sophisticated scoring and sampling methods yielded results which were comparable (Amber score ligand movable protocol) or exceeded (LMOD score) analogous baseline grid-score results. The analysis highlights the potential benefit and challenges associated with including receptor flexibility and indicates that different scoring functions have system dependent strengths and weaknesses. Enrichment studies with the DUD database prepared using the SB2010 preparation protocol and native ligand pairings yielded individual area under the curve (AUC) values derived from receiver operating characteristic curve analysis ranging from 0.29 (bad enrichment) to 0.96 (good enrichment) with an average value of 0.60 (27/38 have AUC ≥ 0.5). Strong early enrichment was also observed in the critically important 1.0-2.0 % region. Somewhat surprisingly, an alternative receptor preparation protocol yielded comparable results. As expected, semi-random pairings yielded poorer enrichments, in particular, for unrelated receptors. Overall, the breadth and number of experiments performed provide a useful snapshot of current capabilities of DOCK6 as well as starting points to guide future development efforts to further improve sampling and scoring.
    Journal of Computer-Aided Molecular Design 05/2012; 26(6):749-73. · 3.17 Impact Factor
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    ABSTRACT: Finding novel antibiotics to combat the rise of drug resistance in harmful bacteria is of enormous importance for human health. Computational drug design can be employed to aid synthetic chemists in the search for new potent inhibitors. In recent years, molecular dynamics based free energy calculations have emerged as a useful tool to accurately calculate receptor binding affinities of novel or modified ligands. While being significantly more demanding in computational resources than simpler docking algorithms, they can be employed to obtain reliable estimates of the effect individual functional groups have on protein-ligand complex binding constants. Beta-ketoacyl [acyl carrier protein] synthase I, KAS I, facilitates a critical chain elongation step in the fatty acid synthesis pathway. Since the bacterial type II lipid synthesis system is fundamentally different from the mammalian type I multi-enzyme complex, this enzyme represents a promising target for the design of specific antibiotics. In this work, we study the binding of several recently synthesized derivatives of the natural KAS I inhibitor thiolactomycin in detail based on atomistic modeling. From extensive thermodynamic integration calculations the effect of changing functional groups on the thiolactone scaffold was determined. Four ligand modifications were predicted to show improved binding to the E. coli enzyme, pointing the way towards the design of thiolactomycin derivatives with binding constants in the nanomolar range.
    Bioorganic & medicinal chemistry 04/2012; 20(11):3446-53. · 2.82 Impact Factor
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    ABSTRACT: Models of early protein evolution posit the existence of short peptides that bound metals and ions and served as transporters, membranes or catalysts. The Cys-X-X-Cys-X-X-Cys heptapeptide located within bacterial ferredoxins, enclosing an Fe₄S₄ metal center, is an attractive candidate for such an early peptide. Ferredoxins are ancient proteins and the simple α+β fold is found alone or as a domain in larger proteins throughout all three kingdoms of life. Previous analyses of the heptapeptide conformation in experimentally determined ferredoxin structures revealed a pervasive right-handed topology, despite the fact that the Fe₄S₄ cluster is achiral. Conformational enumeration of a model CGGCGGC heptapeptide bound to a cubane iron-sulfur cluster indicates both left-handed and right-handed folds could exist and have comparable stabilities. However, only the natural ferredoxin topology provides a significant network of backbone-to-cluster hydrogen bonds that would stabilize the metal-peptide complex. The optimal peptide configuration (alternating α(L),α(R)) is that of an α-sheet, providing an additional mechanism where oligomerization could stabilize the peptide and facilitate iron-sulfur cluster binding.
    PLoS Computational Biology 04/2012; 8(4):e1002463. · 4.83 Impact Factor

Publication Stats

22k Citations
1,141.81 Total Impact Points


  • 2010–2014
    • Rutgers, The State University of New Jersey
      • BioMaPS Institute for Quantitative Biology
      New Brunswick, New Jersey, United States
  • 2013
    • University of Utah
      • Department of Medicinal Chemistry
      Salt Lake City, UT, United States
  • 2011
    • University of Wuerzburg
      • Institute of Inorganic Chemistry
      Würzburg, Bavaria, Germany
    • Karlsruhe Institute of Technology
      • Institute of Physical Chemistry
      Karlsruhe, Baden-Wuerttemberg, Germany
    • Universitetet i Tromsø
      Tromsø, Troms, Norway
  • 1986–2011
    • University of California, Davis
      • Department of Chemistry
      Davis, CA, United States
  • 2009
    • University of California, Berkeley
      • Pitzer Center for Theoretical Chemistry
      Berkeley, CA, United States
  • 1988–2009
    • The Scripps Research Institute
      • Department of Cell and Molecular Biology
      La Jolla, CA, United States
  • 2007
    • University of Naples Federico II
      • Department of Pharmacy
      Napoli, Campania, Italy
  • 2006
    • University Center Rochester
      Rochester, Minnesota, United States
    • Peking University
      Peping, Beijing, China
  • 2005
    • Université de Picardie Jules Verne
      Amiens, Picardie, France
  • 1981–2005
    • University of California, San Diego
      • • Center for Theoretical Biological Physics (CTBP)
      • • Department of Psychology
      San Diego, CA, United States
  • 2003
    • National Chung Hsing University
      • Department of Chemistry
      Taichung, Taiwan, Taiwan
  • 2000
    • 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