Convergence of folding free energy landscapes via application of enhanced sampling methods in a distributed computing environment

We have implemented the serial replica exchange method (SREM) and simulated tempering (ST) enhanced sampling algorithms in a global distributed computing environment. Here we examine the helix-coil transition of a 21 residue alpha-helical peptide in explicit solvent. For ST, we demonstrate the efficacy of a new method for determining initial weights allowing the system to perform a random walk in temperature space based on short trial simulations. These weights are updated throughout the production simulation by an adaptive weighting method. We give a detailed comparison of SREM, ST, as well as standard MD and find that SREM and ST give equivalent results in reasonable agreement with experimental data. In addition, we find that both enhanced sampling methods are much more efficient than standard MD simulations. The melting temperature of the Fs peptide with the AMBER99phi potential was calculated to be about 310 K, which is in reasonable agreement with the experimental value of 334 K. We also discuss other temperature dependent properties of the helix-coil transition. Although ST has certain advantages over SREM, both SREM and ST are shown to be powerful methods via distributed computing and will be applied extensively in future studies of complex bimolecular systems.     

Accelerating molecular dynamic simulation on the cell processor and Playstation 3

Implementation of molecular dynamics (MD) calculations on novel architectures will vastly increase its power to calculate the physical properties of complex systems. Herein, we detail algorithmic advances developed to accelerate MD simulations on the Cell processor, a commodity processor found in PlayStation 3 (PS3). In particular, we discuss issues regarding memory access versus computation and the types of calculations which are best suited for streaming processors such as the Cell, focusing on implicit solvation models. We conclude with a comparison of improved performance on the PS3's Cell processor over more traditional processors.     

Local constancy of dimensions of Hecke eigenspaces of automorphic forms

We use a method of Buzzard to study p-adic families of Hilbert modular forms and modular forms over imaginary quadratic fields. In the case of Hilbert modular forms, we get local constancy of dimensions of spaces of fixed slope and varying weight. For imaginary quadratic fields we obtain bounds independent of the weight on the dimensions of such spaces.     

Parallelized-over-parts computation of absolute binding free energy with docking and molecular dynamics

We present a technique for biomolecular free energy calculations that exploits highly parallelized sampling to significantly reduce the time to results. The technique combines free energies for multiple, nonoverlapping configurational macrostates and is naturally suited to distributed computing. We describe a methodology that uses this technique with docking, molecular dynamics, and free energy perturbation to compute absolute free energies of binding quickly compared to previous methods. The method does not require a priori knowledge of the binding pose as long as the docking technique used can generate reasonable binding modes. We demonstrate the method on the protein FKBP12 and eight of its inhibitors.     

Are Protein Force Fields Getting Better? A Systematic Benchmark on 524 Diverse NMR Measurements

Recent hardware and software advances have enabled simulation studies of protein systems on biophysically-relevant timescales, often revealing the need for improved force fields. Although early force field development was limited by the lack of direct comparisons between simulation and experiment, recent work from several labs has demonstrated direct calculation of NMR observables from protein simulations. Here we quantitatively evaluate recent molecular dynamics force fields against a suite of 524 chemical shift and J coupling ((3)JH(N)H(α), (3)JH(N)C(β), (3)JH(α)C', (3)JH(N)C', and (3)JH(α)N) measurements on dipeptides, tripeptides, tetra-alanine, and ubiquitin. Of the force fields examined (ff96, ff99, ff03, ff03*, ff03w, ff99sb*, ff99sb-ildn, ff99sb-ildn-phi, ff99sb-ildn-nmr, CHARMM27, OPLS-AA), two force fields (ff99sb-ildn-phi, ff99sb-ildn-nmr) combining recent side chain and backbone torsion modifications achieve high accuracy in our benchmark. For the two optimal force fields, the calculation error is comparable to the uncertainty in the experimental comparison. This observation suggests that extracting additional force field improvements from NMR data may require increased accuracy in J coupling and chemical shift prediction. To further investigate the limitations of current force fields, we also consider conformational populations of dipeptides, which were recently estimated using vibrational spectroscopy.     

Empirical force-field assessment: The interplay between backbone torsions and noncovalent term scaling

The kinetic and thermodynamic aspects of the helix-coil transition in polyalanine-based peptides have been studied at the ensemble level using a distributed computing network. This study builds on a previous report, which critically assessed the performance of several contemporary force fields in reproducing experimental measurements and elucidated the complex nature of helix-coil systems. Here we consider the effects of modifying backbone torsions and the scaling of noncovalent interactions. Although these elements determine the potential of mean force between atoms separated by three covalent bonds (and thus largely determine the local conformational distributions observed in simulation), we demonstrate that the interplay between these factors is both complex and force field dependent. We quantitatively assess the heliophilicity of several helix-stabilizing potentials as well as the changes in heliophilicity resulting from such modifications, which can "make or break" the accuracy of a given force field, and our findings suggests that future force field development may need to better consider effect that vary with peptide length. This report also serves as an example of the utility of distributed computing in analyzing and improving upon contemporary force fields at the level of absolute ensemble equilibrium, the next step in force field development.     

Determination of azo compounds with N-bromosuccinimide in acetic acid medium

The bromination reaction of azo compounds with N-bromosuccinimide in acetic acid medium has been studied. Some reaction products have been isolated and reaction mechanisms suggested. The reaction study has been applied for the determination of 2-10 mg of azo compounds. The maximum deviation of the results from the theoretical value is generally within +/- 1%.     

Foldamer dynamics expressed via Markov state models. II. State space decomposition

The structural landscape of poly-phenylacetylene (pPA), otherwise known as m-phenylene ethynylene oligomers, has been shown to consist of a very diverse set of conformations, including helices, turns, and knots. Defining a state space decomposition to classify these conformations into easily identifiable states is an important step in understanding the dynamics in relation to Markov state models. We define the state decomposition of pPA oligomers in terms of the sequence of discretized dihedral angles between adjacent phenyl rings along the oligomer backbone. Furthermore, we derive in mathematical detail an approach to further reduce the number of states by grouping symmetrically equivalent states into a single parent state. A more challenging problem requires a formal definition for knotted states in the structural landscape. Assuming that the oligomer chain can only cross the ideal helix path once, we propose a technique to define a knotted state derived from a helical state determined by the position along the helical nucleus where the chain crosses the ideal helix path. Several examples of helical states and knotted states from the pPA 12-mer illustrate the principles outlined in this article.     

Analytical aspects of organic acids

Summary Phenyl acetic acid has been found to be a selective reagent for the estimation of zirconium. The acid gives a white crystalline precipitate which is quantitative between pH values of 3.00 to 5.40. As the composition of the precipitate varies somewhat, direct weighing is not possible and the compound is ignited to the oxide. The ions Be²⁺, Ca²⁺, Sr²⁺, Zn²⁺, Hg²⁺, Pb²⁺, Mg²⁺, Ni²⁺, and Co²⁺ do not interfere, whereas the ions Fe³⁺, UO₂ ²⁺, Cr³⁺, Ba²⁺, Au⁺, Al³⁺, V₂O₄ ²⁺, Ti⁴⁺, Sn²⁺, and Ba²⁺ cause interferences in the estimation.

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Zusammenfassung Zur gravimetrischen Bestimmung von Zirkonium wird Phenylessigsäure empfohlen. Die weiße, kristalline Fällung ist im pH-Bereich 3,00–5,40 quantitativ. Infolge schwankender Zusammensetzung des Niederschlages ist eine direkte Wägung nicht möglich; er wird daher zum Oxid verglüht. Folgende Ionen stören nicht: Be²⁺, Ca²⁺, Sr²⁺, Zn²⁺, Hg²⁺, Pb²⁺, Mg²⁺, Ni²⁺ und Co²⁺; dagegen verursachen Fe³⁺, UO₂ ²⁺, Cr³⁺, Ba²⁺, Au⁺, Al³⁺, V₂O₄ ²⁺, Ti⁴⁺, Sn²⁺ und Ba²⁺ Störungen bei der Bestim mung.

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Part VI: See Z. analyt. Chem. 175, 29 (1960).     

Direct calculation of the binding free energies of FKBP ligands

Direct calculations of the absolute free energies of binding for eight ligands to FKBP protein were performed using the Fujitsu BioServer massively parallel computer. Using the latest version of the general assisted model building with energy refinement (AMBER) force field for ligand model parameters and the Bennett acceptance ratio for computing free-energy differences, we obtained an excellent linear fit between the calculated and experimental binding free energies. The rms error from a linear fit is 0.4 kcal/mol for eight ligand complexes. In comparison with a previous study of the binding energies of these same eight ligand complexes, these results suggest that the use of improved model parameters can lead to more predictive binding estimates, and that these estimates can be obtained with significantly less computer time than previously thought. These findings make such direct methods more attractive for use in rational drug design.