Showing papers by "David A. Case published in 2003"

Force fields for protein simulations

Abstract: Publisher Summary The chapter focuses on a general description of the force fields that are most commonly used at present, and it gives an indication of the directions of current research that may yield better functions in the near future. After a brief survey of current models, mostly generated during the 1990s, the focus of the chapter is on the general directions the field is taking in developing new models. The most commonly used protein force fields incorporate a relatively simple potential energy function: The emphasis is on the use of continuum methods to model the electrostatic effects of hydration and the introduction of polarizability to model the electronic response to changes in the environment. Some of the history and performance of widely used protein force fields based on an equation on simplest potential energy function or closely related equations are reviewed. The chapter outlines some promising developments that go beyond this, primarily by altering the way electrostatic interactions are treated. The use of atomic multipoles and off-center charge distributions, as well as attempts to incorporate electronic polarizability, are also discussed in the chapter.

Free energy calculations for theophylline binding to an RNA aptamer: Comparison of MM-PBSA and thermodynamic integration methods.

Abstract: We have applied the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method (J. Srinivasan, T. E. Cheatham, P. Cieplak, P. A. Kollman, and D. A. Case, Journal of the American Chemical Society, 1998, Vol. 120, pp. 9401-9409) to study the interaction of an RNA aptamer with theophylline and its analogs. The MM-PBSA free energy analysis provides a reasonable absolute binding free energy for the RNA aptamer-theophylline complex formation. Energetic analysis reveals that the van der Waals interaction and the nonpolar contribution to solvation provide the basis for the favorable absolute free energy of complex. This trend is similar to other protein-ligand interactions studied previously. The MM-PBSA method also ranks the relative binding energies of five theophylline analogs approximately correctly, but not as well as the more conventional thermodynamic integration calculations, which were carried out to convert theophylline into its analogs. The comparison of MM-PBSA with TI suggests that the MM-PBSA method has some difficulties with the first-solvation-shell energetics.

Density Functional and Reduction Potential Calculations of Fe4S4 Clusters

Abstract: Density functional theory geometry optimizations and reduction potential calculations are reported for all five known oxidation states of [Fe4S4(SCH3)4]n- (n = 0, 1, 2, 3, 4) clusters that form the active sites of iron−sulfur proteins. The geometry-optimized structures tend to be slightly expanded relative to experiment, with the best comparison found in the [Fe4S4(SCH3)4]2- model cluster, having bond lengths 0.03 A longer on average than experimentally observed. Environmental effects are modeled with a continuum dielectric, allowing the solvent contribution to the reduction potential to be calculated. The calculated protein plus solvent effects on the reduction potentials of seven proteins (including high potential iron proteins, ferredoxins, the iron protein of nitrogenase, and the “X”, “A”, and “B” centers of photosystem I) are also examined. A good correlation between predicted and measured absolute reduction potentials for each oxidation state of the cluster is found, both for relative potentials wit...

Structural, spectroscopic, and redox consequences of a central ligand in the FeMoco of nitrogenase: a density functional theoretical study.

Abstract: Broken symmetry density functional and electrostatics calculations have been used to shed light on which of three proposed atoms, C, N, or O, is most likely to be present in the center of the FeMoco, the active site of nitrogenase. At the Mo4+4Fe2+3Fe3+ oxidation level, a central N3- anion results in (1) calculated Fe−N bond distances that are in very good agreement with the recent high-resolution X-ray data of Einsle et al.; (2) a calculated redox potential of 0.19 eV versus the standard hydrogen electrode (SHE) for FeMoco(oxidized) + e- → FeMoco(resting), in good agreement with the measured value of −0.042 V in Azotobacter vinelandii; and (3) average Mossbauer isomer shift values (ISav = 0.48 mm s-1) compatible with experiment (ISav = 0.40 mm s-1). At the more reduced Mo4+6Fe2+1Fe3+ level, the calculated geometry around a central N3- anion still correlates well with the X-ray data, but the average Mossbauer isomer shift value (ISav = 0.54 mm s-1) and the redox potential of −2.21 eV show a much poorer ag...

Symmetry and Bonding in metalloporphyrins. A modern implementation for the Bonding analyses of five- and six-coordinate high-spin iron(III)-porphyrin complexes through density functional calculation and NMR spectroscopy

Abstract: Bonding interactions between the iron and the porphyrin macrocycle of five- and six-coordinate high-spin iron(III)−porphyrin complexes are analyzed within the framework of approximate density functional theory with the use of the quantitative energy decomposition scheme in combination with removal of the vacant π* orbitals of the porphyrin from the valence space. Although the relative extent of the iron−porphyrin interactions can be evaluated qualitatively through the spin population and orbital contribution analyses, the bond strengths corresponding to different symmetry representations can be only approximated quantitatively by the orbital interaction energies. In contrast to previous suggestions, there are only limited Fe → P π* back-bonding interactions in high-spin iron(III)−porphyrin complexes. It is the symmetry-allowed bonding interaction between dz2 and a2u orbitals that is responsible for the positive π spin densities at the meso-carbons of five-coordinate iron(III)−porphyrin complexes. Both fiv...

Reintroducing electrostatics into protein X-ray structure refinement: bulk solvent treated as a dielectric continuum.

Abstract: Structural refinement of proteins involves the minimization of a target function that combines X-ray data with a set of restraints enforcing stereochemistry and packing. Electrostatic interactions are not ordinarily included in the target function, partly because they cannot be calculated reliably without a description of dielectric screening by solvent in the crystal. With the recent development of accurate implicit solvent models to describe this screening, the question arises as to whether a more detailed target function including electrostatic and solvation terms can yield more accurate structures or somewhat different structures of equivalent accuracy. The Generalized Born (GB) model is one such model that describes the solvent as a dielectric continuum, taking into account its heterogeneous distribution within the crystal. It is used here for X-ray refinements of three protein structures with experimental diffraction data to 2.4, 2.9 and 3.2 A, respectively. In each case, a higher resolution structure is available for comparison. The new target function includes stereochemical restraints, van der Waals, Coulomb and solvation interactions, along with the usual X-ray pseudo-energy term, which employs the likelihood estimator of Pannu and Read. Multiple simulated-annealing refinements were performed in torsion-angle space with a conventional target function and the new GB target function, yielding ensembles of refined structures. The new target function yields structures of similar accuracy, as measured by the free R factor, map/model correlations and deviations from the high-resolution structures. About 10% of side-chain conformations differ between the two sets of refinements, in the sense that the two ensembles of conformations do not completely overlap. Over 75% of the differences correspond to surface side chains. For one of the proteins, the GB set has a greater dispersion, indicating that for this case the conventional target function overestimates the true precision. As GB parameterization continues to improve, we expect that this approach will become increasingly useful.

A novel method for finding tRNA genes.

Abstract: We describe a novel procedure for generating and optimizing pattern descriptors that can be used to find structural motifs in DNA or RNA sequences. This combines a pattern-description language (based primarily on secondary structure alignment and conservation of some key nucleotides) with a scoring function that relies heavily on estimated folding free energies for the secondary structure of interest. For the cloverleaf secondary structure characteristic of tRNA, we show that a fairly simple pattern descriptor can find almost all known tRNA genes in both bacterial and eukaryotic genomes, and that false positives (sequences that match the pattern but that are probably not tRNAs) can be recognized by their high estimated folding free energies. A general procedure for optimizing descriptors (and hence for finding new structural motifs) is also described. For six bacterial, four eukaryotic, and four archaea genome sequences, our results compare favorably with those of the more complex and specialized tRNAscan-SE algorithm. Prospects for using this general approach to find other RNA structural motifs are discussed.

The circumsphere as a tool to assess distortion in [4Fe-4S] atom clusters.

Abstract: The geometry proposition that "four points not in a plane describe one and only one sphere" provides a novel tool for analyzing protein-induced distortions in [4Fe-4S] clusters. A geometrically perfect reference structure comprises interlaced, regular tetrahedra of Fe, S, and Sγ atoms having T d symmetry. Three circumspheres are defined by the three sets of four atoms, the circumcenters of which are unique points within the cluster. The structure is thus re-defined by the positions of the circumcenters in xyz space and the r, θ, φ of each atom on its respective sphere. Analysis of 12 high-resolution structures of protein-bound and small molecule [4Fe-4S](SR)4 clusters revealed: (a) the circumcenters are generally non-coincident by ~0.01 to ~0.06 A; (b) the Fe radius, rFe, is nominally independent of core oxidation state, having values between 1.66 to 1.69 A, whereas rS and rSG, which have ranges of 2.18–2.24 A and 3.87–3.94 A, respectively, both increase by as much as ~3% upon reduction from the 3+ to the 1+ core valence; (c) deviation of some atoms from the θ, φ of a perfect tetrahedron can be large, ~10°, and sets of atoms can show patterns of motion on their spheres that result from changes in Fe-S bond lengths. Density functional theory calculations suggest that the [4Fe-4S] core itself requires rather little energy to distort (~2 kcal/mol), whereas significantly more energy is required to distort the Sγ shell (~4 kcal/mol) to that of cluster I in Clostridium acidurici ferredoxin.

Rules and problem solving: another look.

Abstract: College students were trained on problems similar to the water jar problems developed by Luchins (1942). Some students were instructed that a particular rule would solve all the problems, others had the same problems but were not instructed about the rule, and a third set of students had a series of novel problems in which no single rule operated throughout. In two experiments students in the instructed rule group not only performed best in training but also performed best when transferred to a condition in which a single novel rule was appropriate. Although results from the set of conditions most similar to those of Luchins suggested that students sometimes inappropriately persisted in rule usage, the overall results suggest that rigidity is not a necessary outcome of instructed problem solving. Indeed, many of the results were consistent with the notion that instructed problem solving is flexible problem solving.

Drug-Target Binding Forces: Advances in Force Field Approaches

Abstract: This article discusses the basic physical chemical principles that determine the strength of non-covalent interactions between ligands and receptors. We consider the basic thermodynamic principles involved in association and consider how molecular mechanics force fields can be helpful in understanding such phenomena. Three examples are discussed in some detail: biotin-avidin, trimethoprim-dihydrofolate reductase, and intercalator-DNA interactions. Keywords: thermodynamics; protein-ligand interactions; force fields; molecular dynamics; free energy