David A Case

University of Leeds, Leeds, England, United Kingdom

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Publications (299)1503.56 Total impact

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    ABSTRACT: We present parmbsc1, a force field for DNA atomistic simulation, which has been parameterized from high-level quantum mechanical data and tested for nearly 100 systems (representing a total simulation time of ∼140 μs) covering most of DNA structural space. Parmbsc1 provides high-quality results in diverse systems. Parameters and trajectories are available at http://mmb.irbbarcelona.org/ParmBSC1/.
    Full-text · Article · Nov 2015 · Nature Methods
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    ABSTRACT: Proper treatment of nonbonded interactions is essential for the accuracy of molecular dynamics (MD) simulations, especially in studies of lipid bilayers. The use of the CHARMM36 force field (C36 FF) in different MD simulation programs can result in disagreements with published simulations performed with CHARMM due to differences in the protocols used to treat the long-range and 1-4 nonbonded interactions. In this study, we systematically test the use of the C36 lipid FF in NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM. A wide range of Lennard-Jones (LJ) cutoff schemes and integrator algorithms were tested to find the optimal simulation protocol to best match bilayer properties of six lipids with varying acyl chain saturation and head groups. MD simulations of a 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) bilayer were used to obtain the optimal protocol for each program. MD simulations with all programs were found to reasonably match the DPPC bilayer properties (surface area per lipid, chain order parameters, and area compressibility modulus) obtained using the standard protocol used in CHARMM as well as from experiments. The optimal simulation protocol was then applied to the other five lipid simulations and resulted in excellent agreement between results from most simulation programs as well as with experimental data. AMBER compared least favorably with the expected membrane properties, which appears to be due to its use of the hard-truncation in the LJ potential versus a force-based switching function used to smooth the LJ potential as it approaches the cutoff distance. The optimal simulation protocol for each program has been implemented in CHARMM-GUI. This protocol is expected to be applicable to the remainder of the additive C36 FF including the proteins, nucleic acids, carbohydrates, and small molecules.
    Full-text · Article · Nov 2015 · Journal of Chemical Theory and Computation
  • Iwen Fu · David A Case · Jean Baum
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    ABSTRACT: In the canonical (G-X-Y)n sequence of the fibrillar collagen triple helix, stabilizing direct inter-chain hydrogen bonding connects neighboring chains. Mutations at G can disrupt these interactions and are linked to connective tissue diseases. Here we integrate computational approaches with NMR to obtain a dynamic view of hydrogen bonding distributions in the (POG)4-(POA)-(POG)5 peptide, showing that the solution conformation, dynamics and hydrogen bonding deviate from the reported x-ray crystal structure in many aspects. The simulations and NMR data provide clear evidence for inequivalent environments in the three chains. MD simulations indicate direct inter-chain hydrogen bonds in the leading chain, water-bridges in the middle chain, and non-bridging waters in the trailing chain at the G→A substitution site. Theoretical calculations of NMR chemical shifts using a quantum fragmentation procedure can account for the unusual downfield NMR chemical shifts at the substitution sites and are used to assign the resonances to the individual chains. The NMR and MD data highlight the sensitivity of amide shifts to changes in the acceptor group from peptide carbonyls to water. The results are used to interpret solution NMR data for a variety of glycine substitutions and other sequence triplet interruptions, to provide new connections between collagen sequences, their associated structures, dynamical behavior and ability to recognize collagen receptors.
    No preview · Article · Sep 2015 · Biochemistry
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    ABSTRACT: Approaches that combine experimental data and computational molecular (MD) dynamics to determine atomic resolution ensembles of biomolecules require the measurement of abundant experimental data. NMR residual dipolar couplings (RDCs) carry rich dynamics information, however, difficulties in modulating overall alignment of nucleic acids has limited the ability to fully extract this information. We present a strategy for modulating RNA alignment that is based on introducing variable dynamic kinks in terminal helices. With this strategy, we measured seven sets of RDCs in a cUUCGg apical loop and used this rich data set to test the accuracy of an 0.8 μs molecular dynamics simulation computed using the Amber ff10 force field as well as to determine an atomic resolution ensemble. The MD-generated ensemble quantitatively reproduces the measured RDCs but selection of a sub-ensemble was required to satisfy the RDCs within error. The largest discrepancies between the RDC-selected and MD-generated ensembles are observed for the most flexible loop residues and backbone angles connecting the loop to the helix, with the RDC-selected ensemble resulting in more uniform dynamics. Comparison of the RDC-selected ensemble with NMR spin relaxation data suggests that the dynamics occurs on the ps-ns timescales as verified by measurements of R1ρ relaxation-dispersion data. The RDC-satisfying ensemble samples many conformations adopted by the hairpin in crystal structures indicating that intrinsic plasticity may play important roles in conformational adaptation. The approach presented here can be applied to test nucleic acid force fields and to characterize dynamics in diverse RNA motifs at atomic resolution.
    No preview · Article · Aug 2015 · Journal of the American Chemical Society
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    ABSTRACT: The composition of the ion atmosphere surrounding nucleic acids affects their folding, condensation and binding to other molecules. It is thus of fundamental importance to gain predictive insight into the formation of the ion atmosphere and thermodynamic consequences when varying ionic conditions. An early step toward this goal is to benchmark computational models against quantitative experimental measurements. Herein, we test the ability of the three dimensional reference interaction site model (3D-RISM) to reproduce preferential interaction parameters determined from ion counting (IC) experiments for mixed alkali chlorides and dsDNA. Calculations agree well with experiment with slight deviations for salt concentrations >200 mM and capture the observed trend where the extent of cation accumulation around the DNA varies inversely with its ionic size. Ion distributions indicate that the smaller, more competitive cations accumulate to a greater extent near the phosphoryl groups, penetrating deeper into the grooves. In accord with experiment, calculated IC profiles do not vary with sequence, although the predicted ion distributions in the grooves are sequence and ion size dependent. Calculations on other nucleic acid conformations predict that the variation in linear charge density has a minor effect on the extent of cation competition. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
    Full-text · Article · Aug 2015 · Nucleic Acids Research
  • Jason Swails · Tong Zhu · Xiao He · David A Case
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    ABSTRACT: We evaluate the performance of the automated fragmentation quantum mechanics/molecular mechanics approach (AF-QM/MM) on the calculation of protein and nucleic acid NMR chemical shifts. The AF-QM/MM approach models solvent effects implicitly through a set of surface charges computed using the Poisson-Boltzmann equation, and it can also be combined with an explicit solvent model through the placement of water molecules in the first solvation shell around the solute; the latter substantially improves the accuracy of chemical shift prediction of protons involved in hydrogen bonding with solvent. We also compare the performance of AF-QM/MM on proteins and nucleic acids with two leading empirical chemical shift prediction programs SHIFTS and SHIFTX2. Although the empirical programs outperform AF-QM/MM in predicting chemical shifts, the differences are in some cases small, and the latter can be applied to chemical shifts on biomolecules which are outside the training set employed by the empirical programs, such as structures containing ligands, metal centers, and non-standard residues. The AF-QM/MM described here is implemented in version 5 of the SHIFTS software, and is fully automated, so that only a structure in PDB format is required as input.
    No preview · Article · Aug 2015 · Journal of Biomolecular NMR
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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.
    No preview · Article · Jun 2015 · Journal of Computational Chemistry
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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.
    Full-text · Article · Jun 2015 · Nature Structural & Molecular Biology
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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.
    Full-text · Article · May 2015 · Science
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    David A Case

    Preview · Article · May 2015 · Journal of biomolecular Structure & Dynamics
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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.
    No preview · Article · May 2015 · Protein Science
  • 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.
    No preview · Article · Mar 2015 · RNA
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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.
    Full-text · Article · Dec 2014 · The Journal of Chemical Physics
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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.
    Preview · Article · Oct 2014 · Journal of Chemical Theory and Computation
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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.
    Full-text · Article · Sep 2014 · Nucleic Acids Research
  • 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.
    No preview · Article · Sep 2014 · Biochimica et Biophysica Acta (BBA) - General Subjects
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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.
    Full-text · Article · Feb 2014 · Biophysical Journal
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    Article: Amber 14

    Full-text · Article · Jan 2014
  • Article: Amber 14

    No preview · Article · Jan 2014
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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.
    Full-text · Article · Jul 2013 · Journal of Structural Biology

Publication Stats

41k Citations
1,503.56 Total Impact Points


  • 2015
    • University of Leeds
      • School of Physics and Astronomy
      Leeds, England, United Kingdom
  • 2009-2015
    • Rutgers, The State University of New Jersey
      • • BioMaPS Institute for Quantitative Biology
      • • Department of Chemical 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
      • • Department of Chemistry
      La Jolla, California, United States
  • 2008
    • Université de Picardie Jules Verne
      Amiens, Picardie, France
  • 2005
    • 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
      臺中市, Taiwan, Taiwan
  • 2001
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • University of Alberta
      Edmonton, Alberta, Canada
  • 1999-2000
    • University of California, San Diego
      • Department of Psychology
      San Diego, CA, United States
  • 1997
    • Torrey Pines Institute for Molecular Studies
      Port St. Lucie, Florida, United States
  • 1993
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1980-1989
    • University of California, Davis
      • Department of Chemistry
      Davis, California, United States
  • 1976-1979
    • Harvard University
      Cambridge, Massachusetts, United States