Calculation of affinities of peptides for proteins

Several methodologies were employed to calculate the Gibbs standard free energy of binding for a collection of protein-ligand complexes, where the ligand is a peptide and the protein is representative for various protein families. Almost 40 protein-ligand complexes were employed for a continuum approach, which considers the protein and the peptide at the atomic level, but includes solvent as a polarizable continuum. Five protein-ligand complexes were employed for an all-atom approach that relies on a combination of the double decoupling method with thermodynamic integration and molecular dynamics. These affinities were also computed by means of the linear interaction energy method. Although it generally proved rather difficult to predict the absolute free energies correctly, for some protein families the experimental ranking order was correctly reproduced by the continuum and all-atom approach. Considerable attention has also been given to correctly analyze the affinities of charged peptides, where it is required to judge the effect of one or more ions that are being decoupled in an all-atom approach to preserve electroneutrality. The various methods are further judged upon their merits.     

Improving the efficiency and reliability of free energy perturbation calculations using overlap sampling methods

A challenge in free energy calculation for complex molecular systems by computer simulation is to obtain a reliable estimate within feasible computational time. In this study, we suggest an answer to this challenge by exploring a simple method, overlap sampling (OS), for producing reliable free-energy results in an efficient way. The formalism of the OS method is based on ensuring sampling of important overlapping phase space during perturbation calculations. This technique samples both forward and reverse free energy perturbation (FEP) to improve the free-energy calculation. It considers the asymmetry of the FEP calculation and features an ability to optimize both the precision and the accuracy of the measurement without affecting the simulation process itself. The OS method is tested at two optimization levels: no optimization (simple OS), and full optimization (equivalent to Bennett's method), and compared to conventional FEP techniques, including the widely used direct FEP averaging method, on three alchemical mutation systems: (a) an anion transformation in water solution, (b) mutation between methanol and ethane, and (c) alchemical change of an adenosine molecule. It is consistently shown that the reliability of free-energy estimates can be greatly improved using the OS techniques at both optimization levels, while the performance of Bennett's method is particularly striking. In addition, the efficiency of a calculation can be significantly improved because the method is able to (a) converge to the right answer quickly, and (b) work for large perturbations. The basic two-stage OS method can be extended to admit additional stages, if needed. We suggest that the OS method can be used as a general perturbation technique for computing free energy differences in molecular simulations.     

Calculating the energies for Ag(001) twist boundaries utilizing the modified analytical embedded atom method

The unrelaxed energies for Ag(001) twist grain boundaries (GBs) have been calculated using the modified analytical embedded atom method (MAEAM). The results show that, besides zero energy in a perfect crystal (corresponding to the twist angle 0°), the second smallest GB energy corresponds to the twist angle 36.87°. This is consistent with the experimental results. For other twist angles, the GB energies remain nearly constant even for a twist angle as small as 1.94°. Translation parallel to the boundary plane could result in a periodic change in GB energy. Copyright © 2004 John Wiley & Sons, Ltd.     

Characterization of a Poly(2‐oxazoline) Library by High‐Throughput,Automated Contact‐Angle Measurements and Surface‐Energy Calculations

Summary: The feasibility of automated, high‐throughput contact‐angle measurements is demonstrated using a modified commercial contact‐angle measuring apparatus. Droplets are automatically dispensed, analyzed and aspirated. The system automatically measures more than 100 contact angles per hour using two test liquids, and calculates surface energies using the equation of state method. A library of poly(2‐oxazoline) homo‐ and block copolymers was investigated. Polymers with a 2‐nonyl‐2‐oxazoline block were found to have considerably lower surface energies.

Setup used here for characterization of the surface properties of a library of poly(2‐oxazoline) homo‐ and block copolymers.     

Kinetics of photoreduction of 9,10-phenanthrenequinone in the presence of amines and polymethylbenzenes

A study of the kinetics of photoreduction of 9,10-phenanthrenequinone in the presence of hydrogen donors (para-substituted N,N-dimethylanilines and polymethylbenzenes) showed that plots of the quantum yield of photoreduction (_H) and apparent reaction rate constant (k _H) vs. oxidation potential of hydrogen donors are extreme. In the presence of amines, k _H and _H increase, as a whole, whereas they decrease in the presence of polymethylbenzenes. In coordinates _H-G _e (G _e is the change in the free energy of electron transfer) for pairs quinone-H donor, _H increases with G _e approaching to zero. For the amine series, this effect is mainly in the exothermic region of G _e (G _e < 0). For the series of polymethylbenzenes, this increase is observed in the endothermic region (G _e > 0).__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2381–2385, November, 2004.     

Ab initio and DFT studies on hydrolyses of phosphorus halides

Hydrolyses of phosphorus halides, (RO)(2)POX where R = H or Me and X = F or Cl, in the gas phase and in the reaction field have been investigated theoretically with ab initio and the density functional theory (DFT). The free energy of activation in the reaction field was also estimated using the Onsager method with a correction of entropy change and basis set superposition error (BSSE). The reaction of (MeO)(2)POF proceeds through a path with bifunctional catalysis regardless of the medium, but the reaction of (MeO)(2)POCl proceeds through bifunctional and general base catalysis in the gas phase and in water, respectively. The estimated free energy barrier of 23 kcal/mol for the hydrolysis of (MeO)(2)POF is in good agreement with the experimental values of 24 kcal/mol, and relative barrier of 3 kcal/mol to the (MeO)(2)POCl is also in good agreement with the experimental values of 5 kcal/mol of diisopropyl phosphorus halides ((Pr(i)O)(2)POX, X = F and Cl).