New scoring functions for virtual screening from molecular dynamics simulations with a quantum-refined force-field (QRFF-MD). Application to cyclin-dependent kinase 2.

A recently introduced new methodology based on ultrashort (50-100 ps) molecular dynamics simulations with a quantum-refined force-field (QRFF-MD) is here evaluated in its ability both to predict protein-ligand binding affinities and to discriminate active compounds from inactive ones. Physically based scoring functions are derived from this approach, and their performance is compared to that of several standard knowledge-based scoring functions. About 40 inhibitors of cyclin-dependent kinase 2 (CDK2) representing a broad chemical diversity were considered. The QRFF-MD method achieves a correlation coefficient, R(2), of 0.55, which is significantly better than that obtained by a number of traditional approaches in virtual screening but only slightly better than that obtained by consensus scoring (R(2) = 0.50). Compounds from the Available Chemical Directory, along with the known active compounds, were docked into the ATP binding site of CDK2 using the program Glide, and the 650 ligands from the top scored poses were considered for a QRFF-MD analysis. Combined with structural information extracted from the simulations, the QRFF-MD methodology results in similar enrichment of known actives compared to consensus scoring. Moreover, a new scoring function is introduced that combines a QRFF-MD based scoring function with consensus scoring, which results in substantial improvement on the enrichment profile.

The chemistry of water on alumina surfaces: reaction dynamics from first principles

Aluminas and their surface chemistry play a vital role in many areas of modern technology. The behavior of adsorbed water is particularly important and poorly understood. Simulations of hydrated alpha-alumina (0001) surfaces with ab initio molecular dynamics elucidate many aspects of this problem, especially the complex dynamics of water dissociation and related surface reactions. At low water coverage, free energy profiles established that molecularly adsorbed water is metastable and dissociates readily, even in the absence of defects, by a kinetically preferred pathway. Observations at higher water coverage revealed rapid dissociation and unanticipated collective effects, including water-catalyzed dissociation and proton transfer reactions between adsorbed water and hydroxide. The results provide a consistent interpretation of the measured coverage dependence of water heats of adsorption, hydroxyl vibrational spectra, and other experiments.

Computational approach to the physical chemistry of fullerenes and their derivatives.

A critical review is presented of results obtained with different computational methods (mainly ab initio) on C60, C70, and specific fullerene derivatives, also in comparison with experimental data. From the discussion of diverse systems, the (often underestimated) complexity of their physical and chemical behavior emerges, and hence the importance of an accurate description and the need for a careful inspection of the experimental data, with which comparison is often intrinsically difficult. The ambition of this review is to help establish a basis not only for a nonsuperficial reading of the existing literature, but also for a constructive approach with computations to the challenge posed by recent promising applications of fullerenes in nanotechnology, optoelectronics, and biology.

Structural and electronic properties of la@c82.

The structural and electronic properties of the La@C(82) fullerene have been investigated by means of the Car-Parrinello method, which is based on the local density approximation of the density functional theory. The topological arrangement of the C(82) cage was assumed to be a C(3v) symmetry isomer. Three configurations were considered, one with the lanthanum atom at the center of the cluster, one with it along the threefold axis, and one with it at a low-symmetry, highly coordinated site. The structure was fully relaxed and it was found that the last of these configurations is energetically preferred. In this position, the lanthanum atom is nearly in a La(3+) state and the unpaired electron is somewhat delocalized on the cage, in agreement with available experimental data. This arrangement suggests that the chemical shifts of the 5s and 5p lanthanum states can be used as a structural probe and as a way of further validating this picture. It is argued that this conclusion is not affected by the assumed fullerene structure.