David A Case

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

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Publications (236)949.28 Total impact

  • [Show abstract] [Hide abstract]
    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. · 3.67 Impact Factor
  • Biopolymers 07/2013; · 2.88 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; · 3.36 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; · 2.88 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; · 10.68 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; · 8.74 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; · 3.61 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. · 3.16 Impact Factor
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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 01/2013; · 10.68 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. · 5.39 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. · 4.87 Impact Factor
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    ABSTRACT: The reference interaction site model (RISM) provides complete equilibrium sampling of bulk solvent and solvent around a solute of arbitrary shape and size at a fraction of the computational cost of explicit solvent molecular dynamics (MD). Though based on first principles, approximations must be made to achieve numerical solutions. In this study, we first compare RISM to MD and experimental results for bulk solutions of aqueous monovalent ions using the Joung-Cheatham parameters with SPC/E and TIP3P water subject to several approximate closures. Then, using the same parameters and approximations, we evaluate the distribution of water and ions around a 24 base pair strand of DNA, once again, comparing to MD results and experimental observables. In both cases RISM gives the correct qualitative behavior and, often, the correct quantitative behavior. However, this strongly depends on the closure relation used, with higher order, HNC-like closures usually giving better results.
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    Junchao Xia, David A Case
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    ABSTRACT: Although the crystal structure of the disaccharide sucrose was solved more than 30 years ago, its conformational distribution in aqueous solution is still a matter of debate. We report here a variety of molecular dynamics simulations (mostly of 100 ns) using the GLYCAM06 force field and various water models, paying particular attention to comparisons to NMR measurements of residual dipolar couplings and electron-mediated spin-spin couplings. We focus on the glycosidic linkage conformation, the puckering phase angle of the fructose ring, and intramolecular hydrogen bonds between the two sugars. Our results show that sucrose is indeed a dynamic molecule, but the crystal conformation is qualitatively the dominant one in dilute solution. A second conformational basin, populated in many force fields, is probably overstabilized in the calculations.
    Biopolymers 12/2011; 97(5):276-88. · 2.88 Impact Factor
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    ABSTRACT: Molecular dynamics-based free energy calculations allow the determination of a variety of thermodynamic quantities from computer simulations of small molecules. Thermodynamic integration (TI) calculations can suffer from instabilities during the creation or annihilation of particles. This "singularity" problem can be addressed with "soft-core" potential functions which keep pairwise interaction energies finite for all configurations and provide smooth free energy curves. "One-step" transformations, in which electrostatic and van der Waals forces are simultaneously modified, can be simpler and less expensive than "two-step" transformations in which these properties are changed in separate calculations. Here, we study solvation free energies for molecules of different hydrophobicity using both models. We provide recommended values for the two parameters α(LJ) and β(C) controlling the behavior of the soft-core Lennard-Jones and Coulomb potentials and compare one- and two-step transformations with regard to their suitability for numerical integration. For many types of transformations, the one-step procedure offers a convenient and accurate approach to free energy estimates.
    Journal of Computational Chemistry 11/2011; 32(15):3253-63. · 3.84 Impact Factor
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    ABSTRACT: The human severe acute respiratory syndrome coronavirus (SARS-CoV) and the NL63 coronaviruses are human respiratory pathogens for which no effective antiviral treatment exists. The papain-like cysteine proteases encoded by the coronavirus (SARS-CoV: PLpro; NL63: PLP1 and PLP2) represent potential targets for antiviral drug development. Three recent inhibitor-bound PLpro structures highlight the role of an extremely flexible six-residue loop in inhibitor binding. The high binding site plasticity is a major challenge in computational drug discovery/design efforts. From conventional molecular dynamics and accelerated molecular dynamics (aMD) simulations, we find that with conventional molecular dynamics simulation, PLpro translationally samples the open and closed conformation of BL2 loop on a picosecond-nanosecond timescale but does not reproduce the peptide bond inversion between loop residues Tyr269 and Gln270 that is observed on inhibitor GRL0617 binding. Only aMD simulation, starting from the closed loop conformation, reproduced the 180° ϕ-ψ dihedral rotation back to the open loop state. The Tyr-Gln peptide bond inversion appears to involve a progressive conformational change of the full loop, starting at one side, and progressing to the other. We used the SARS-CoV apo X-ray structure to develop a model of the NL63-PLP2 catalytic site. Superimposition of the PLP2 model on the PLpro X-ray structure identifies binding site residues in PLP2 that contribute to the distinct substrate cleavage site specificities between the two proteases. The topological and electrostatic differences between the two protease binding sites also help explain the selectivity of non-covalent PLpro inhibitors.
    Journal of Molecular Biology 11/2011; 414(2):272-88. · 3.91 Impact Factor
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    Junchao Xia, David A Case
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    ABSTRACT: We report 100 ns molecular dynamics simulations, at various temperatures, of sucrose in water (with concentrations of sucrose ranging from 0.02 to 4M), and in a 7:3 water-DMSO mixture. Convergence of the resulting conformational ensembles was checked using adaptive-biased simulations along the glycosidic Φ and ψ torsion angles. NMR relaxation parameters, including longitudinal (R₁) and transverse (R₂) relaxation rates, nuclear Overhauser enhancements (NOE), and generalized order parameter (S²) were computed from the resulting time-correlation functions. The amplitude and time scales of molecular motions change with temperature and concentration in ways that track closely with experimental results, and are consistent with a model in which sucrose conformational fluctuations are limited (with 80-90% of the conformations having ϕ-ψ values within 20° of an average conformation), but with some important differences in conformation between pure water and DMSO-water mixtures.
    Biopolymers 11/2011; 97(5):289-302. · 2.88 Impact Factor
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    Thomas Gaillard, David A Case
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    ABSTRACT: DNA structural deformations and dynamics are crucial to its interactions in the cell. Theoretical simulations are essential tools to explore the structure, dynamics, and thermodynamics of biomolecules in a systematic way. Molecular mechanics force fields for DNA have benefited from constant improvements during the last decades. Several studies have evaluated and compared available force fields when the solvent is modeled by explicit molecules. On the other hand, few systematic studies have assessed the quality of duplex DNA models when implicit solvation is employed. The interest of an implicit modeling of the solvent consists in the important gain in the simulation performance and conformational sampling speed. In this study, respective influences of the force field and the implicit solvation model choice on DNA simulation quality are evaluated. To this end, extensive implicit solvent duplex DNA simulations are performed, attempting to reach both conformational and sequence diversity convergence. Structural parameters are extracted from simulations and statistically compared to available experimental and explicit solvation simulation data. Our results quantitatively expose the respective strengths and weaknesses of the different DNA force fields and implicit solvation models studied. This work can lead to the suggestion of improvements to current DNA theoretical models.
    Journal of Chemical Theory and Computation 10/2011; 7(10):3181-3198. · 5.39 Impact Factor
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    ABSTRACT: The typical workflow for NMR structure determination involves collecting thousands of conformational restraints, calculating a bundle of 20-40 conformers in agreement with them and refining the energetics of these conformers. The structure calculation step employs simulated annealing based on molecular dynamics (MD) simulations with very simplified force fields. The value of refining the calculated conformers using restrained MD (rMD) simulations with state-of-art force fields is documented. This refinement however presents various subtleties, from the proper formatting of conformational restraints to the definition of suitable protocols. We describe a web interface to set up and run calculations with the AMBER package, which we called AMPS-NMR (AMBER-based Portal Server for NMR structures). The interface allows the refinement of NMR structures through rMD. Some predefined protocols are provided for this purpose, which can be personalized; it is also possible to create an entirely new protocol. AMPS-NMR can handle various restraint types. Standard rMD refinement in explicit water of the structures of three different proteins are shown as examples. AMPS-NMR additionally includes a workspace for the user to store different calculations. As an ancillary service, a web interface to AnteChamber is available, enabling the calculation of force field parameters for organic molecules such as ligands in protein-ligand adducts. AMPS-NMR is embedded within the NMR services of the WeNMR project and is available at http://py-enmr.cerm.unifi.it/access/index/amps-nmr; its use requires registration with a digital certificate. ivanobertini@cerm.unifi.it Supplementary data are available at Bioinformatics online.
    Bioinformatics 09/2011; 27(17):2384-90. · 5.47 Impact Factor

Publication Stats

16k Citations
949.28 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
  • 1990–2005
    • 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
  • 1998
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 1997
    • Torrey Pines Institute for Molecular Studies
      Port St. Lucie, Florida, United States