Showing papers by "David A. Case published in 2008"
TL;DR: Performance has been improved to the point where using QM/MM, for a QM system of 71 atoms within an explicitly solvated protein using periodic boundaries and PME requires less than twice the cpu time of the corresponding classical simulation.
Abstract: Version 9 of the Amber simulation programs includes a new semi-empirical hybrid QM/MM functionality. This includes support for implicit solvent (generalized Born) and for periodic explicit solvent simulations using a newly developed QM/MM implementation of the particle mesh Ewald (PME) method. The code provides sufficiently accurate gradients to run constant energy QM/MM MD simulations for many nanoseconds. The link atom approach used for treating the QM/MM boundary shows improved performance, and the user interface has been rewritten to bring the format into line with classical MD simulations. Support is provided for the PM3, PDDG/PM3, PM3CARB1, AM1, MNDO, and PDDG/MNDO semi-empirical Hamiltonians as well as the self-consistent charge density functional tight binding (SCC-DFTB) method. Performance has been improved to the point where using QM/MM, for a QM system of 71 atoms within an explicitly solvated protein using periodic boundaries and PME requires less than twice the cpu time of the corresponding classical simulation. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008
350 citations
TL;DR: This study demonstrates that the analysis of the MIECs between peptides and the SH3 domain can successfully characterize the binding interface, and it provides a framework to derive integrated prediction models for different domain-peptide systems.
191 citations
TL;DR: This work re-ranked docking hit lists in three small buried sites in molecular mechanics-generalized Born surface area techniques, and rescoring not only rescued docking false positives, but also introduced several new false positives into the top-ranking molecules.
181 citations
TL;DR: A method for extracting diffusion tensors from such simulations of proteins in water that are long compared to the overall tumbling of the molecule is described and the results to experimental values extracted from NMR relaxation measurements are compared.
Abstract: It is now feasible to carry out molecular dynamics simulations of proteins in water that are long compared to the overall tumbling of the molecule. Here, we examine rotational diffusion in four small, globular proteins (ubiquitin, binase, lysozyme, and fragment B3 of protein G) with the TIP3P, TIP4P/EW, and SPC/E water models, in simulations that are 6 to 60 times as long as the mean rotational tumbling time. We describe a method for extracting diffusion tensors from such simulations and compare the results to experimental values extracted from NMR relaxation measurements. The simulation results accurately follow a diffusion equation, even for spherical harmonic correlation functions with l as large as 8. However, the best-fit tensors are significantly different from experiment, especially for the commonly used TIP3P water model. Simulations that are 20 to 100 times longer than the rotational tumbling times are needed for good statistics. A number of residues exhibit internal motions on the nanosecond time scale, but in all cases examined here, a product of internal and overall time-correlation functions matches the total time-correlation function well.
140 citations
TL;DR: This application of DFT generally conforms with previously suggested criteria for a valid model and shows how the chemistry of O 2 reduction in the heme a 3 -Cu B dinuclear center can be harnessed to generate an electrochemical proton gradient across the lipid bilayer.
Abstract: A mechanism for proton pumping by the B-type cytochrome c oxidases is presented in which one proton is pumped in conjunction with the weakly exergonic, two-electron reduction of Fe-bound O2 to the Fe−Cu bridging peroxodianion and three protons are pumped in conjunction with the highly exergonic, two-electron reduction of Fe(III)−−O−O−−Cu(II) to form water and the active oxidized enzyme, Fe(III)−−OH,Cu(II). The scheme is based on the active-site structure of cytochrome ba3 from Thermus thermophilus, which is considered to be both necessary and sufficient for coupled O2 reduction and proton pumping when appropriate gates are in place (not included in the model). Fourteen detailed structures obtained from density functional theory (DFT) geometry optimization are presented that are reasonably thought to occur during the four-electron reduction of O2. Each proton-pumping step takes place when a proton resides on the imidazole ring of I-His376 and the large active-site cluster has a net charge of +1 due to an u...
61 citations
TL;DR: D duplex DNAs with three different bases opposite an abasic site have been synthesized in the same sequence context and molecular dynamics simulations reveal that transient H-bond interactions between the unpaired pyrimidine and the base 3′ to the abAsic site play an important role in perturbing the local conformation.
Abstract: Abasic sites are common DNA lesions resulting from spontaneous depurination and excision of damaged nucleobases by DNA repair enzymes. However, the influence of the local sequence context on the structure of the abasic site and ultimately, its recognition and repair, remains elusive. In the present study, duplex DNAs with three different bases (G, C or T) opposite an abasic site have been synthesized in the same sequence context (5′-CCA AAG6 XA8C CGG G-3′, where X denotes the abasic site) and characterized by 2D NMR spectroscopy. Studies on a duplex DNA with an A opposite the abasic site in the same sequence has recently been reported [Chen,J., Dupradeau,F.-Y., Case,D.A., Turner,C.J. and Stubbe,J. (2007) Nuclear magnetic resonance structural studies and molecular modeling of duplex DNA containing normal and 4′-oxidized abasic sites. Biochemistry, 46, 3096–3107]. Molecular modeling based on NMR-derived distance and dihedral angle restraints and molecular dynamics calculations have been applied to determine structural models and conformational flexibility of each duplex. The results indicate that all four duplexes adopt an overall B-form conformation with each unpaired base stacked between adjacent bases intrahelically. The conformation around the abasic site is more perturbed when the base opposite to the lesion is a pyrimidine (C or T) than a purine (G or A). In both the former cases, the neighboring base pairs (G6-C21 and A8-T19) are closer to each other than those in B-form DNA. Molecular dynamics simulations reveal that transient H-bond interactions between the unpaired pyrimidine (C20 or T20) and the base 3′ to the abasic site play an important role in perturbing the local conformation. These results provide structural insight into the dynamics of abasic sites that are intrinsically modulated by the bases opposite the abasic site.
61 citations
TL;DR: Three different binding modes at single iron site and three different BS-DFT spin state structures are considered and it is shown that this binding would enhance the key hyperfine signal A(iso)(X) by at least 1 order of magnitude.
Abstract: Broken symmetry density functional theory (BS-DFT) has been used to address the hyperfine parameters of the single atom ligand X, proposed to be coordinated by six iron ions in the center of the paramagnetic FeMo-cofactor (FeMoco) of nitrogenase. Using the X = N alternative, we recently found that any hyperfine signal from X would be small (calculated Aiso(X = 14N) = 0.3 MHz) due to both structural and electronic symmetry properties of the [Mo−7Fe−9S−X] FeMoco core in its resting S = 3/2 state. Here, we extend our BS-DFT approach to the 2e− reduced S = 1/2 FeMoco state. Alternative substrates coordinated to this FeMoco state effectively perturb the electronic and/or structural symmetry properties of the cofactor. Using an example of an allyl alcohol (H2C═CH−CH2−OH) product ligand, we consider three different binding modes at single iron site and three different BS-DFT spin state structures and show that this binding would enhance the key hyperfine signal Aiso(X) by at least 1 order of magnitude (3.8 ≤ Ais...
55 citations
TL;DR: In this paper, an atomistic QM/MM approach based on a one-electron tight binding Hamiltonian and a classical molecular mechanics forcefield was employed to conduct nanosecond length MD simulations of electron holes in DNA oligomers.
Abstract: The electron transfer properties of DNA radical cations are important in DNA damage and repair processes. Fast long-range charge transfer has been demonstrated experimentally, but the subtle influences that experimental conditions as well as DNA sequences and geometries have on the details of electron transfer parameters are still poorly understood. In this work, we employ an atomistic QM/MM approach, based on a one-electron tight binding Hamiltonian and a classical molecular mechanics forcefield, to conduct nanosecond length MD simulations of electron holes in DNA oligomers. Multiple spontaneous electron transfer events were observed in 100 ns simulations with neighboring adenine or guanine bases. Marcus parameters of charge transfer could be extracted directly from the simulations. The reorganization energy λ for hopping between neighboring bases was found to be ca. 25 kcal/mol and charge transfer rates of 4.1 × 109 s−1 for AA hopping and 1.3 × 109 s−1 for GG hopping were obtained.
54 citations
TL;DR: The results confirm the sensitivity of the carbon-deuterium bonds to their local protein environment, demonstrate that dihydrofolate reductase is electrostatically and dynamically heterogeneous, and lay the foundation for the direct characterization protein electrostatics and dynamics and, potentially, their contribution to catalysis.
Abstract: Much effort has been directed toward understanding the contributions of electrostatics and dynamics to protein function and especially to enzyme catalysis. Unfortunately, these studies have been limited by the absence of direct experimental probes. We have been developing the use of carbon−deuterium bonds as probes of proteins and now report the application of the technique to the enzyme dihydrofolate reductase, which catalyzes a hydride transfer and has served as a paradigm for biological catalysis. We observe that the stretching absorption frequency of (methyl-d3) methionine carbon−deuterium bonds shows an approximately linear dependence on solvent dielectric. Solvent and computational studies support the empirical interpretation of the stretching frequency in terms of local polarity. To begin to explore the use of this technique to study enzyme function and mechanism, we report a preliminary analysis of (methyl-d3) methionine residues within dihydrofolate reductase. Specifically, we characterize the IR...
50 citations
TL;DR: The elastic rod theory is used together with all‐atom normal mode analysis in implicit solvent to characterize the mechanical flexibility of duplex DNA and CTG and CGG trinucleotide repeats are found to be more flexible than random DNA, in agreement with several recent studies.
Abstract: The elastic rod theory is used together with all-atom normal mode analysis in implicit solvent to characterize the mechanical flexibility of duplex DNA. The bending, twisting, stretching rigidities extracted from all-atom simulations (on linear duplexes from 60 to 150 base pairs in length and from 94-bp minicircles) are in reasonable agreement with experimental results. We focus on salt concentration and sequence effects on the overall flexibility. Bending persistence lengths are about 20% higher than most experimental estimates, but the transition from low-salt to high-salt behavior is reproduced well, as is the dependence of the stretching modulus on salt (which is opposite to that of bending). CTG and CGG trinucleotide repeats, responsible for several degenerative disorders, are found to be more flexible than random DNA, in agreement with several recent studies, whereas poly(dA).poly(dT) is the stiffest sequence we have encountered. The results suggest that current all-atom potentials, which were parameterized on small molecules and short oligonucleotides, also provide a useful description of duplex DNA at much longer length scales.
33 citations
TL;DR: The occurrence of complex alleles may be an alternative explanation for the variability of the phenotype in individuals who are compound heterozygous for c.[187C>G]+[845G>A] (p.[His63Asp]+[Cys282Tyr]).
Abstract: Most adults affected with HFE hereditary hemochromatosis (HH type 1, MIMmusical sharp 235200) are homozygous for the p.Cys282Tyr mutation in HFE (NC_000006.10, region 26195427 to 26205038). The aim of this study was to investigate the molecular basis of iron overload in a patient presenting with severe clinical HH with one c.845G>A (p.Cys282Tyr) allele only. Molecular and pedigree studies demonstrated the presence of the c.845G>A (p.Cys282Tyr) mutation in one allele whereas the other carried the c.187C>G (p.His63Asp) mutation plus a new c.128G>A (p.Gly43Asp) substitution in cis. A molecular modeling study of the p.[Gly43Asp;His63Asp] and p.His63Asp variants versus the wild type was carried out using molecular dynamics (MD) simulation in presence of implicit solvent. We found that the c.187C>G (p.His63Asp) mutation does not introduce any major change in the 1- domains of HFE whereas the c.128G>A (p.Gly43Asp) substitution is responsible for a modification of the dynamics and the structure of the Gln40-Ser45 loop, a critical region for HFE-TfR1 interaction thus impairing HFE-TfR1 normal contact. We conclude that the occurrence of complex alleles may be an alternative explanation for the variability of the phenotype in individuals who are compound heterozygous for c.[187C>G]+[845G>A] (p.[His63Asp]+[Cys282Tyr]).
TL;DR: In this paper, the authors survey recent progress in this direction, focusing on internal motions of protein backbones and side-chains, and overall rotational diffusion, and provide important pointers on how to carry out MD simulations with increased fidelity to the underlying structure and dynamics of the systems being studied.
Abstract: NMR spin-relaxation (in either small molecules or in biomolecules) can provide unique insights into to the time-dependence of conformational fluctuations, especially on picosecond to nanosecond time scales which can be directly probed by simulations. A great deal has been learned from molecular dynamics simulations about the general nature of such motions and their impact on NMR observables. In principle, relaxation measurements should also provide valuable benchmarks for judging the quantitative accuracy of simulations, and we survey recent progress in this direction, focusing on internal motions of protein backbones and side-chains, and overall rotational diffusion. Such information provides important pointers on how to carry out MD simulations with increased fidelity to the underlying structure and dynamics of the systems being studied.