The second virial coefficient, A 2 , is evaluated between pairs of short chain molecules by direct simulations using a parallel tempering Monte Carlo method where the centers of mass of the two molecules are coupled by a harmonic spring. Three off-lattice polymer models are considered, one with rigid bonds and two with flexible bonds, represented by the finitely extensible nonlinear elastic potential with different stiffness. All the models considered account for excluded volume interactions via the Lennard-Jones potential. In order to obtain the second virial coefficient we calculate the effective intermolecular interaction between the two polymer chains. As expected this intermolecular interaction is found to be strongly dependent upon chain length and temperature. For all three models the temperature (n), defined as the temperature at which the second virial coefficient vanishes for chains of finite length, varies as n Ϫ ϱ ϰn Ϫ1/2 , where n is the number of bonds in the polymer chains and ϱ is the point for an infinitely long chain. Introducing flexibility into the model has two effects upon n ; the temperature is reduced with increasing flexibility, and the n dependence of n is suppressed. For a particular choice of spring constant an n-independent temperature is found. We also compare our results with those obtained from experimental studies of polystyrene in decalin and cyclohexane, and for poly͑methyl methacrylate͒ in a water and tert-butyl alcohol mixture, and show that all the data can be collapsed onto a single universal curve without any adjustable parameters. We are thus able to relate both A 2 and the excluded volume parameter v, to the chain interaction parameter z, in a way relating not only the data for different molecular weights and temperatures, but also for different polymers in different solvents.

We present a new molecular dynamics methodology to assist in structure-based drug design and other studies that seek to predict protein deformability. Termed Active Site Pressurization (ASP), the new methodology simply injects a resin into the ligand binding-site of a protein during the course of a molecular dynamics simulation such that novel, energetically reasonable protein conformations are generated in an unbiased way that may be better representations of the ligand binding conformation than are currently available. Here we apply two different versions of the ASP methodology to three proteins, cytochrome P450cam, PcrA helicase, and glycogen synthase kinase 3beta (GSK3beta), and show that the method is capable of inducing significant conformational changes when compared to the X-ray crystal structures. Application of the ASP methodology therefore provides a view of binding site flexibility that is a rich source of data for inclusion in a variety of further investigations, including high-throughput virtual screening, lead hopping, revealing alternative modes of deformation, and revealing hidden exit and entrance tunnels.

Comment on "Monte Carlo simulations of smectic phase transitions in flexible-rigid-flexible molecules" [J. Chem. Monte Carlo study of a semiflexible liquid crystal model: The smectic phaseWe present comprehensive results from constant NVT and constant NPT Monte Carlo simulations of particles interacting via a biaxial variant of the Gay-Berne potential which we term the Internally Rotated Gay-Berne ͑IRGB͒ potential. The IRGB potential may be considered to be a single-site approximation to the interaction between two zig-zag shaped molecules, the extent of this molecular biaxiality being characterized by an internal rotation angle ␦. We find that increasing the value of ␦ frustrates the formation of orientationally ordered phases, all phase transitions being shifted to lower temperatures and higher densities. Additionally, for ␦у30 degrees, the smectic B phase is replaced by the tilted smectic J phase. The smectic A phase, in contrast, is destabilized completely for sufficiently large ␦, with neither smectic A nor its tilted equivalent, smectic C, being observed. This suggests that models for smectic C-formation which are based on biaxial intermolecular attractions may not offer the best route to obtaining this phase.

GSK3beta (glycogen synthase kinase 3beta) is involved in the phosphorylation of various important regulatory proteins. Pharmacological inhibition of this enzyme could yield treatments for a variety of diseases including diabetes and Alzheimer's disease. The understanding of events involved in the molecular recognition of inhibitors by the active site of this enzyme is key in structure-based design strategies. The present study deals with the dynamic nature of GSK3beta and highlights the importance of studying protein plasticity in structure-based drug design, exemplified by our method called ASP (active-site pressurization).

A new 3D-QSAR method based on the novel molecular dynamics methodology, Active Site Pressurization (ASP), has been validated using two cyclin-dependent kinase 2 data sets containing 65 purines and 91 oxindoles. ASP allows the construction of cavity casts that represent the maximal energetically feasible 3D distortion of protein binding sites potentially achievable by induced fit upon binding of ligands. The ASP-QSAR method entails many components of traditional 3D-QSAR strategies but additionally correlates the biological activity of ligand sets with features of ASP-derived binding site cavity casts, thus taking target protein flexibility into account implicitly. Both of the data sets used to validate the ASP-QSAR method resulted in QSAR models that were of exceptional quality and predictivity. A non-cross-validated variance coefficient (R 2 ) between 0.959 and 0.99 and a cross-validated variance coefficient (Q 2 ) of between 0.927 and 0.929 were obtained for these ASP-QSAR models.