Missing mass analysis of the A−2 at 6.0 GeV/c

The missing mass spectrum in the region of the A^?₂ has been measured in the reaction π^?p→X^?p at 6.0 GeV/c in the interval 0.27 <|t|<0.42 (GeV/c)², with an optical spark chamber system which simultaneously observed the decay X^?→ηπ^?. A signal of 230 events above background per five MeV interval is observed at the A₂ peak, with a signal-to-background ratio of greater than 1:1. A single D-wave Breit-Wigner distribution with a quadratic background gives a good fit to the data, yielding the parameters M₀=(1.324±0.003) GeV/c² and Γ₀=(0.104±0.009) GeV/c². The spectrum is incompatible with a dipole shape.     

Let’s get honest about sampling

Molecular simulations see widespread and increasing use in computation and molecular design, especially within the area of molecular simulations applied to biomolecular binding and interactions, our focus here. However, force field accuracy remains a concern for many practitioners, and it is often not clear what level of accuracy is really needed for payoffs in a discovery setting. Here, I argue that despite limitations of today’s force fields, current simulation tools and force fields now provide the potential for real benefits in a variety of applications. However, these same tools also provide irreproducible results which are often poorly interpreted. Continued progress in the field requires more honesty in assessment and care in evaluation of simulation results, especially with respect to convergence.     

Review of Chemometrics Applied to Spectroscopy: 1985-95, Part 3 — Multi-way Analysis

INTRODUCTION

In this third part of a review on chemometrics in spectroscopy we will describe a recent methodology that has attracted increasing interest in spectroscopy. namely multi-way analysis. The application of multi-way analysis in spectroscopy is still relatively new. hence many methodological improvements are being investigated currently. Part of thls review will also be used to describe the algorithmic improvements gained the last decade.     

Physical and chemical evolution of PMDA-ODA during thermal imidization

The processing of poly(imide) films from poly(amic acid) solutions involves the simultaneous loss of solvent and chemical conversion, and may involve structural reorganization such as orientation or crystallization. Here, we describe weight loss, solvent sorption. Fourier transform infrared (FTIR), and wide-angle x-ray scattering (WAXS) studies during thermal imidization of the commercially important poly(imide) PMDA-ODA. The results indicate that imidization proceeds nearly to completion before significant crystallization occurs. The experimental data are interpreted in terms of a triangular phase diagram that makes it possible to plot the processing pathway during the conversion from poly(amic acid) solution to solid poly(imide). In constructing this triangular phase diagram the extent of imidization (i.e., the composition of the poly(amic acid-co-imide) copolymers during conversion) is treated as an independent thermodynamic variable. The form of the triangular phase diagram can be predicted from the Flory-Huggins lattice theory of mixing. There is inevitably a two-phase region present due to the relatively poor solubility of the poly(imide) in the poly(amic acid) solvent (NMP). The specific processing pathway taken depends on the relative amount of solvent loss and imidization during conversion. Further details about the triangular phase diagrams of poly(imides) will require such studies as solvent swelling at intermediate stages of conversion. © 1995 John Wiley & Sons, Inc.     

Charge asymmetries in hydration of polar solutes

We study the solvation of polar molecules in water. The center of water's dipole moment is offset from its steric center. In common water models, the Lennard-Jones center is closer to the negatively charged oxygen than to the positively charged hydrogens. This asymmetry of water's charge sites leads to different hydration free energies of positive versus negative ions of the same size. Here, we explore these hydration effects for some hypothetical neutral solutes, and two real solutes, with molecular dynamics simulations using several different water models. We find that, like ions, polar solutes are solvated differently in water depending on the sign of the partial charges. Solutes having a large negative charge balancing diffuse positive charges are preferentially solvated relative to those having a large positive charge balancing diffuse negative charges. Asymmetries in hydration free energies can be as large as 10 kcal/mol for neutral benzene-sized solutes. These asymmetries are mainly enthalpic, arising primarily from the first solvation shell water structure. Such effects are not readily captured by implicit solvent models, which respond symmetrically with respect to charge.     

NMR Spectroscopic Structural Determination of Organozinc Reagents: Evidence for “Highly Coordinated” Zincates

The structures of ¹³ C-labeled methylzinc reagents have been studied by NMR spectroscopy. Analysis of the spectra gives information on the number of chemically equivalent methyl groups that are attached to the metal centers. Shown is the structure of trimethylzincate with the spin couplings that form the basis of the spin system used in the calculation.     

Variation in FPOP Measurements Is Primarily Caused by Poor Peptide Signal Intensity

Fast photochemical oxidation of proteins (FPOP) may be used to characterize changes in protein structure by measuring differences in the apparent rate of peptide oxidation by hydroxyl radicals. The variability between replicates is high for some peptides and limits the statistical power of the technique, even using modern methods controlling variability in radical dose and quenching. Currently, the root cause of this variability has not been systematically explored, and it is unknown if the major source(s) of variability are structural heterogeneity in samples, remaining irreproducibility in FPOP oxidation, or errors in LC-MS quantification of oxidation. In this work, we demonstrate that coefficient of variation of FPOP measurements varies widely at low peptide signal intensity, but stabilizes to ≈?0.13 at higher peptide signal intensity. We dramatically reduced FPOP variability by increasing the total sample loaded onto the LC column, indicating that the major source of variability in FPOP measurements is the difficulties in quantifying oxidation at low peptide signal intensities. This simple method greatly increases the sensitivity of FPOP structural comparisons, an important step in applying the technique to study subtle conformational changes and protein-ligand interactions.

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Graphical Abstract ?

     

Blind prediction of cyclohexane–water distribution coefficients from the SAMPL5 challenge

In the recent SAMPL5 challenge, participants submitted predictions for cyclohexane/water distribution coefficients for a set of 53 small molecules. Distribution coefficients (log D) replace the hydration free energies that were a central part of the past five SAMPL challenges. A wide variety of computational methods were represented by the 76 submissions from 18 participating groups. Here, we analyze submissions by a variety of error metrics and provide details for a number of reference calculations we performed. As in the SAMPL4 challenge, we assessed the ability of participants to evaluate not just their statistical uncertainty, but their model uncertainty—how well they can predict the magnitude of their model or force field error for specific predictions. Unfortunately, this remains an area where prediction and analysis need improvement. In SAMPL4 the top performing submissions achieved a root-mean-squared error (RMSE) around 1.5 kcal/mol. If we anticipate accuracy in log D predictions to be similar to the hydration free energy predictions in SAMPL4, the expected error here would be around 1.54 log units. Only a few submissions had an RMSE below 2.5 log units in their predicted log D values. However, distribution coefficients introduced complexities not present in past SAMPL challenges, including tautomer enumeration, that are likely to be important in predicting biomolecular properties of interest to drug discovery, therefore some decrease in accuracy would be expected. Overall, the SAMPL5 distribution coefficient challenge provided great insight into the importance of modeling a variety of physical effects. We believe these types of measurements will be a promising source of data for future blind challenges, especially in view of the relatively straightforward nature of the experiments and the level of insight provided.     

Treating entropy and conformational changes in implicit solvent simulations of small molecules

Implicit solvent models are increasingly popular for estimating aqueous solvation (hydration) free energies in molecular simulations and other applications. In many cases, parameters for these models are derived to reproduce experimental values for small molecule hydration free energies. Often, these hydration free energies are computed for a single solute conformation, neglecting solute conformational changes upon solvation. Here, we incorporate these effects using alchemical free energy methods. We find significant errors when hydration free energies are estimated using only a single solute conformation, even for relatively small, simple, rigid solutes. For example, we find conformational entropy (TDeltaS) changes of up to 2.3 kcal/mol upon hydration. Interestingly, these changes in conformational entropy correlate poorly (R2 = 0.03) with the number of rotatable bonds. The present study illustrates that implicit solvent modeling can be improved by eliminating the approximation that solutes are rigid.