A.H. de Vries

Enantioselective catalytic conjugate addition of dialkylzinc reagents using copper-phosphoramidite complexes; Ligand variation and non-linear effects

Abstract A variety of new chiral phosphoramidites was synthesised and tested in the copper-catalysed enantioselective conjugate addition of diethylzinc to cyclohexenone and chalcone in order to assess the structural features that are important for stereocontrol. A sterically demanding amine moiety is essential to reach high e.e.’s. Enantioselectivities for chalcones up to 89% and for cyclic enones up to 98% were found. Studies on non-linear effects with the best ligands for both cyclohexenone and chalcone showed clear non-linear effects for both cyclic and acyclic enones.

Direct reaction field force field: A consistent way to connect and combine quantum-chemical and classical descriptions of molecules

The direct reaction field (DRF) force field gives a classical description of intermolecular interactions based on ab initio quantum-chemical descriptions of matter. The parameters of the DRF force field model molecular electrostatic and response properties, which are represented by distributed charges and dipole polarizabilities. The advantage of the DRF force field is that it can be combined transparently with quantum-chemical descriptions of a part of a large system, such as a molecule in solution or an active site in a protein. In this study, the theoretical basis for the derivation of the parameters is reviewed, paying special attention to the four interaction components: electrostatic, induction, dispersion, and repulsion. The ability of the force field to provide reliable intermolecular interactions is assessed, both in its mixed quantum-chemical-classical and fully classical usage. Specifically, the description of the water dimer and the solvation of water in water is scrutinized and seen to perform well. The force field is also applied to systems of a very different nature, viz. the benzene dimer and substituted-benzene dimers, as well as the acetonitrile and tetrachloromethane dimers. Finally, the solvation of a number of polar solutes in water is investigated. It is found that as far as the interaction energy is concerned, the DRF force field provides a reliable embedding scheme for molecular environments. The calculation of thermodynamic properties, such as solvation energy, requires better sampling of phase space than applied here

X-ray structure of bovine pancreatic phospholipase A2 at atomic resolution

Using synchrotron radiation and a CCD camera, X-ray data have been collected from wild-type bovine pancreatic phospholipase A(2) at 100 K to 0.97 A resolution allowing full anisotropic refinement. The final model has a conventional R factor of 9.44% for all reflections, with a mean standard uncertainty for the positional parameters of 0.031 A as calculated from inversion of the full positional least-squares matrix. At 0.97 A resolution, bovine pancreatic phospholipase A(2) reveals for the first time that its rigid scaffolding does not preclude flexibility, which probably plays an important role in the catalytic process. Functionally important regions (the interfacial binding site and calcium-binding loop) are located at the molecular surface, where conformational variability is more pronounced. A cluster of 2-methyl-2,4-pentanediol molecules is present at the entrance of the hydrophobic channel that leads to the catalytic site and mimics the fatty-acid chains of a substrate analogue. Bovine pancreatic phospholipase A(2) at atomic resolution is compared with previous crystallographic structures and with models derived from nuclear magnetic resonance studies. Given the high structural similarity among extracellular phospholipases A(2) observed so far at lower resolution, the results arising from this structural analysis are expected to be of general validity for this class of enzymes.

Methods for Multiscale Modeling of Membranes

Multiscale modeling is a recent approach to simulating molecular systems, such as membranes and liposomes, in which different levels of detail are combined. By using distinct models, it is often possible to speed up or enrich the sampling of a given system. Examples are the use in molecular dynamics simulations of both coarse-grained and fine-grained representations, either simultaneously or alternating in time or space domains. Another possible example is the combination of Monte Carlo and molecular dynamics simulations. This chapter reviews the existing proposed methods of multiscale modeling and simulation and also presents new insights into this fascinating new trend.