Showing papers by "David A. Case published in 2006"

Automatic atom type and bond type perception in molecular mechanical calculations.

Abstract: In molecular mechanics (MM) studies, atom types and/or bond types of molecules are needed to determine prior to energy calculations. We present here an automatic algorithm of perceiving atom types that are defined in a description table, and an automatic algorithm of assigning bond types just based on atomic connectivity. The algorithms have been implemented in a new module of the AMBER packages. This auxiliary module, antechamber (roughly meaning "before AMBER"), can be applied to generate necessary inputs of leap-the AMBER program to generate topologies for minimization, molecular dynamics, etc., for most organic molecules. The algorithms behind the manipulations may be useful for other molecular mechanical packages as well as applications that need to designate atom types and bond types.

An accurate and simple quantum model for liquid water.

Abstract: The path-integral molecular dynamics and centroid molecular dynamics methods have been applied to investigate the behavior of liquid water at ambient conditions starting from a recently developed simple point charge/flexible (SPC/Fw) model. Several quantum structural, thermodynamic, and dynamical properties have been computed and compared to the corresponding classical values, as well as to the available experimental data. The path-integral molecular dynamics simulations show that the inclusion of quantum effects results in a less structured liquid with a reduced amount of hydrogen bonding in comparison to its classical analog. The nuclear quantization also leads to a smaller dielectric constant and a larger diffusion coefficient relative to the corresponding classical values. Collective and single molecule time correlation functions show a faster decay than their classical counterparts. Good agreement with the experimental measurements in the low-frequency region is obtained for the quantum infrared spectrum, which also shows a higher intensity and a redshift relative to its classical analog. A modification of the original parametrization of the SPC/Fw model is suggested and tested in order to construct an accurate quantum model, called q-SPC/Fw, for liquid water. The quantum results for several thermodynamic and dynamical properties computed with the new model are shown to be in a significantly better agreement with the experimental data. Finally, a force-matching approach was applied to the q-SPC/Fw model to derive an effective quantum force field for liquid water in which the effects due to the nuclear quantization are explicitly distinguished from those due to the underlying molecular interactions. Thermodynamic and dynamical properties computed using standard classical simulations with this effective quantum potential are found in excellent agreement with those obtained from significantly more computationally demanding full centroid molecular dynamics simulations. The present results suggest that the inclusion of nuclear quantum effects into an empirical model for water enhances the ability of such model to faithfully represent experimental data, presumably through an increased ability of the model itself to capture realistic physical effects.

Estimation of Absolute Free Energies of Hydration Using Continuum Methods: Accuracy of Partial Charge Models and Optimization of Nonpolar Contributions.

Abstract: Absolute free energies of hydration (ΔGhyd) for more than 500 neutral and charged compounds have been computed, using Poisson−Boltzmann (PB) and Generalized Born (GB) continuum methods plus a solvent-accessible surface area (SA) term, to evaluate the accuracy of eight simple point-charge models used in molecular modeling. The goal is to develop improved procedures and protocols for protein−ligand binding calculations and virtual screening (docking). The best overall PBSA and GBSA results, in comparison with experimental ΔGhyd values for small molecules, were obtained using MSK, RESP, or ChelpG charges obtained from ab initio calculations using 6-31G* wave functions. Correlations using semiempirical (AM1BCC, AM1CM2, and PM3CM2) or empirical (Gasteiger-Marsili and MMFF94) methods yielded mixed results, particularly for charged compounds. For neutral compounds, the AM1BCC method yielded the best agreement with experimental results. In all cases, the PBSA and GBSA results are highly correlated (overall r2 = 0...

A Multistep Approach to Structure-Based Drug Design: Studying Ligand Binding at the Human Neutrophil Elastase †

Abstract: In this study we show that a combination of different theoretical methods is a viable approach to calculate the binding affinities of new ligands for the human neutrophile elastase. This protease degrades elastin and likely aids neutrophils in fulfilling their immunological functions. Abnormally high human neutrophil elastase (HNE) levels are involved in several diseases; therefore, inhibitors of HNE are of interest as targets for drug design. A recent study has revealed that cinnamic acid and bornyl ester derivatives bind to HNE, but ΔG0 values from ligand docking results exhibited no correlation with those calculated from the IC50 values. To accurately compute binding affinities, we generated possible protein ligand complex structures by ligand docking calculations. For each of the ligands, the 30 most likely placements were used as starting points of nanosecond length molecular dynamics simulations. The binding free energies for these complex structures were estimated using a continuum solvent (MM-PBSA...

How Nitrogenase Shakes – Initial Information about P-Cluster and FeMo-cofactor Normal Modes from Nuclear Resonance Vibrational Spectroscopy (NRVS)

Abstract: Nitrogenase catalyzes a reaction critical for life, the reduction of N(2) to 2NH(3), yet we still know relatively little about its catalytic mechanism. We have used the synchrotron technique of (57)Fe nuclear resonance vibrational spectroscopy (NRVS) to study the dynamics of the Fe-S clusters in this enzyme. The catalytic site FeMo-cofactor exhibits a strong signal near 190 cm(-)(1), where conventional Fe-S clusters have weak NRVS. This intensity is ascribed to cluster breathing modes whose frequency is raised by an interstitial atom. A variety of Fe-S stretching modes are also observed between 250 and 400 cm(-)(1). This work is the first spectroscopic information about the vibrational modes of the intact nitrogenase FeMo-cofactor and P-cluster.

A comparison of quantum chemical models for calculating NMR shielding parameters in peptides: mixed basis set and ONIOM methods combined with a complete basis set extrapolation.

Abstract: This article compares several quantum mechanical approaches to the computation of chemical shielding tensors in peptide fragments. First, we describe the effects of basis set quality up to the complete basis set (CBS) limit and level of theory (HF, MP2, and DFT) for four different atoms in trans N-methylacetamide. For both isotropic shielding and shielding anisotropy, the MP2 results in the CBS limit show the best agreement with experiment. The HF values show quite a different tendency to MP2, and even in the CBS limit they are far from experiment for not only the isotropic shielding of carbonyl carbon but also most shielding anisotropies. In most cases, the DFT values differ systematically from MP2, and small basis-set (double- or triple-zeta) results are often fortuitously in better agreement with the experiment than the CBS ones. Second, we compare the mixed basis set and ONIOM methods, combined with CBS extrapolation, for chemical shielding calculations at a DFT level using various model peptides. From the results, it is shown that the mixed basis set method provides better results than ONIOM, compared to CBS calculations using the nonpartitioned full systems. The information studied here will be useful in guiding the selection of proper quantum chemical models, which are in a tradeoff between accuracy and cost, for shielding studies of peptides and proteins.

Implicit Solvent Electrostatics in Biomolecular Simulation

Abstract: We give an overview of how implicit solvent models are currently used in protein simulations. The emphasis is on numerical algorithms and approximations: since even folded proteins sample many distinct configurations, it is of considerable importance to be both accurate and efficient in estimating the energetic consequences of this dynamical behavior. Particular attention is paid to calculations of pH-dependent behavior, as a paradigm for the analysis of electrostatic interactions in complex systems.

Dynamics of an [Fe4S4(SPh)4]2- cluster explored via IR, Raman, and nuclear resonance vibrational spectroscopy (NRVS)-analysis using 36S substitution, DFT calculations, and empirical force fields.

Abstract: We have used four vibrational spectroscopies--FT-IR, FT-Raman, resonance Raman, and 57Fe nuclear resonance vibrational spectroscopy (NRVS)--to study the normal modes of the Fe-S cluster in [(n-Bu)4N]2[Fe4S4(SPh)4]. This [Fe4S4(SR)4]2- complex serves as a model for the clusters in 4Fe ferredoxins and high-potential iron proteins (HiPIPs). The IR spectra exhibited differences above and below the 243 K phase transition. Significant shifts with 36S substitution into the bridging S positions were also observed. The NRVS results were in good agreement with the low temperature data from the conventional spectroscopies. The NRVS spectra were interpreted by normal mode analysis using optimized Urey-Bradley force fields (UBFF) as well as from DFT theory. For the UBFF calculations, the parameters were refined by comparing calculated and observed NRVS frequencies and intensities. The frequency shifts after 36S substitution were used as an additional constraint. A D 2d symmetry Fe4S4S'4 model could explain most of the observed frequencies, but a better match to the observed intensities was obtained when the ligand aromatic rings were included for a D 2d Fe4S4(SPh)4 model. The best results were obtained using the low temperature structure without symmetry constraints. In addition to stretching and bending vibrations, low frequency modes between approximately 50 and 100 cm(-1) were observed. These modes, which have not been seen before, are interpreted as twisting motions with opposing sides of the cube rotating in opposite directions. In contrast with a recent paper on a related Fe4S4 cluster, we find no need to assign a large fraction of the low frequency NRVS intensity to 'rotational lattice modes'. We also reassign the 430 cm(-1) band as primarily an elongation of the thiophenolate ring, with approximately 10% terminal Fe-S stretch character. This study illustrates the benefits of combining NRVS with conventional Raman and IR analysis for characterization of Fe-S centers. DFT theory is shown to provide remarkable agreement with the experimental NRVS data. These results provide a reference point for the analysis of more complex Fe-S clusters in proteins.

Second derivatives in generalized born theory

Abstract: Generalized Born solvation models offer a popular method of including electrostatic aspects of solvation free energies within an analytical model that depends only upon atomic coordinates, charges, and dielectric radii. Here, we describe how second derivatives with respect to Cartesian coordinates can be computed in an efficient manner that can be distributed over multiple processors. This approach makes possible a variety of new methods of analysis for these implicit solvation models. We illustrate three of these methods here: the use of Newton-Raphson optimization to obtain precise minima in solution; normal mode analysis to compute solvation effects on the mechanical properties of DNA; and the calculation of configurational entropies in the MM/GBSA model. An implementation of these ideas, using the Amber generalized Born model, is available in the nucleic acid builder (NAB) code, and we present examples for proteins with up to 45,000 atoms. The code has been implemented for parallel computers using both the OpenMP and MPI environments, and good parallel scaling is seen with as many as 144 OpenMP processing threads or MPI processing tasks.

Low‐Resolution Molecular Dynamics Simulations of the 30S Ribosomal Subunit

Abstract: Low-resolution molecular models can provide appropriate and efficient ways for studying large biomolecular systems such as the ribosome. We have developed computer codes that use the Yammp Under Python modeling package to assemble low-resolution force fields for RNA-protein complexes, and that connect these to the Amber molecular simulation package. This pipeline combines many of the complementary strengths of these two packages. Our target here is the 30S ribosomal subunit from Thermus thermophilus. One hundred nanosecond Langevin dynamics simulations were performed for the bound and the unbound 16S RNA, and conformational changes of the 16S RNA and its interaction with the 30S proteins were examined to establish the fidelity of our model. The S7 protein assembly pathway was also examined, and the effects of protein binding order on the 16S RNA were analyzed. The simulations suggest that ribosomal proteins play important roles in maintaining the native 16S RNA structure. "Primary" proteins (in terms of assembly) help more in stabilizing the conformation of the RNA than do secondary and tertiary proteins. Ribosomal proteins appear to bind to the RNA in an organized fashion wherein primary and secondary proteins help to prepare the binding sites for tertiary proteins. The methodology and tools described here should provide useful ways to explore other aspects of ribosomal conformational changes by means of molecular dynamics simulations.

Using AMBER to simulate DNA and RNA

Abstract: The use of molecular dynamics and free energy simulation model nucleic acid structure, dynamics, and interactions are discussed from the authors AMBERcentric viewpoint.