A Monte Carlo method for finding important ligand fragments from receptor data

A simulated annealing method for finding important ligand fragments is described. At a given temperature, ligand fragments are randomly selected and randomly placed within the given receptor cavity, often replacing or forming bonds with existing ligand fragments. For each new ligand fragment combination, the bonded, nonbonded, polarization and solvation energies of the new ligand–receptor system are compared to the previous configuration. Acceptance or rejection of the new system is decided using the Boltzmann distribution , where E is the energy difference between the old and new systems, k is the Boltzmann constant and T is the temperature. Thus, energetically unfavorable fragment switches are sometimes accepted, sacrificing immediate energy gains in the interest of finding a system with minimum energy. By lowering the temperature, the rate of unfavorable switches decreases and energetically favorable combinations become more difficult to change. The process is terminated when the frequency of switches becomes too small. As a test, the method predicted positions and types of important ligand fragments for neuraminidase that were in accord with the known ligand, sialic acid.     

PHOTOSENSITIZATION BY DRUGS IN SURFACTANT SOLUTIONS

Abstract— Chlorpromazine, promazine, anthracene and furosemide were tested as photosensitizers using 365 nm UV light in micellar solutions of cationic, anionic and nonionic surfactants. In all cases, micelles enhanced the ability of these compounds to photosensitize the oxidation of 2,5-dimethylfuran and the free radical polymerization of acrylamide. pH variation showed that the base form of chlorpromazine and the acid form of furosemide are the principal photosensitizing forms of these compounds. Rate differences between cationic and anionic surfactant media indicate the cation radical to be the major photochemical species formed from chlorpromazine and promazine in micellar media. Photodechlorination of chlorpromazine accounted for a significantly higher reactivity of chlorpromazine over promazine. Anthracene was found to be a very active photosensitizer by the singlet oxygen mechanism but also yielded a small concentration of cation radicals in micellar solution. In its neutral form, furosemide reacted strongly in both photooxidation and photopolymerization systems.
The implications of this study to drug-induced photosensitivity are that (i) free radical reactions may play a major role, and (ii) these sensitizers are more reactive in a hydrophobic environment, suggesting that the cellular membrane or the hydrophobic surfaces of proteins or DNA are more important sites of action in photosensitivity.     

Ab initio study of catalyzed and uncatalyzed amide bond formation as a model for peptide bond formation: Ammonia-Glycine reactions

As a model reaction for peptide and bond formation, the S_N2 reactions between glycine and ammonia have been studied with and without amine catalysis: using ab initio molecular-orbital methods. For each of the catalyzed and uncatalyzed reactions, two reaction mechanisms have been examined: a two-step and a concerted mechanism. The stationary points of each reaction, including intermediate and transition states, have been identified and free energies calculated for all geometry-optimized reaction species to determine the thermodynamics and kinetics of the reaction. The calculations demonstrate that a second ammonia molecule catalyzes amide bond formation, and that the two-step mechanism is more favorable than the concerted one for the catalyzed reaction, while for the uncatalyzed reaction both mechanisms are competitive.     

Entangled and disentangled evolution for a single atom in a driven cavity

For an atom in an externally driven cavity, we show that special initial states lead to near-disentangled atom-field evolution, and superpositions of these can lead to near maximally entangled states. Somewhat counterintutively, we find that (moderate) spontaneous emission in this system actually leads to a transient increase in entanglement beyond the steady-state value. We also show that a particular field correlation function could be used, in an experimental setting, to track the time evolution of this entanglement.     

alpha- and 3(10)-helix interconversion: a quantum-chemical study on polyalanine systems in the gas phase and in aqueous solvent.

Helices are among the predominant secondary structures in globular proteins. About 90% of the residues in them are found to be in the alpha-helical conformation, and another 10% in the 3(10) conformation. There is a standing controversy between experimental and some theoretical results, and controversy among theoretical results concerning the predominance of each conformation, in particular, helices. We address this controversy by ab initio Hartree-Fock and density functional theory studies of helices with different lengths in a vacuum and in the aqueous phase. Our results show that (1) in a vacuum, all oligo(Ala) helices of 4-10 residues adopt the 3(10) - conformation; (2) in aqueous solution, the 6-10 residue peptides adopt the alpha-helical conformation; (3) there might be two intermediates between these helical conformers allowing for their interconversion. The relevance of these results to the structure and folding of proteins is discussed.