In order to stimulate the development of drugs against severe acute respiratory syndrome (SARS), based on the atomic coordinates of the SARS coronavirus main proteinase determined recently [Science 13 (May) (2003) (online)], studies of docking KZ7088 (a derivative of AG7088) and the AVLQSGFR octapeptide to the enzyme were conducted. It has been observed that both the above compounds interact with the active site of the SARS enzyme through six hydrogen bonds. Also, a clear definition of the binding pocket for KZ7088 has been presented. These findings may provide a solid basis for subsite analysis and mutagenesis relative to rational design of highly selective inhibitors for therapeutic application. Meanwhile, the idea of how to develop inhibitors of the SARS enzyme based on the knowledge of its own peptide substrates (the so-called "distorted key" approach) was also briefly elucidated.

No abstract

In this paper the ab initio potential of mean force for the formic acid-water system is calculated in a Monte Carlo simulation using a classical fluctuating charge molecular mechanics potential to guide Monte Carlo updates. The ab initio energies in the simulation are calculated using density-functional theory ͑DFT͒ methods recently developed by Salahub et al. ͓J. Chem. Phys. 107, 6770 ͑1997͔͒ to describe hydrogen-bonded systems. Importance sampling methods are used to investigate structural changes and it is demonstrated that using a molecular mechanics importance function can improve the efficiency of a DFT simulation by several orders of magnitude. Monte Carlo simulation of the system in a canonical ensemble at Tϭ300 K reveals two chemical processes at intermediate time scales: The rotation of the H 2 O bonded to HCOOH, which takes place on a time scale of 3 ps, and the dissociation of the complex which occurs in 24 ps. It is shown that these are the only important structural ''reactions'' in the formic acid-water cluster which take place on a time scale shorter than the double transfer of the proton.

An ab initio molecular dynamics simulation technique is developed employing the Born–Oppenheimer (BO) approach in the framework of a Gaussian implementation of Kohn–Sham density functional theory (DFT). Simulation results for H5O2+ at 200 K are reported. The density profiles, autocorrelation functions and power spectra are presented. The anharmonic frequencies at 200 K are found to be close to the harmonic frequencies calculated directly from quantum methods at 0 K. Structures of large hydrated proton clusters are optimized. Simulated annealing techniques were employed to search for low energy structures and found to be very useful for clusters with 7–8 water molecules. A few very different structures with ground state energy 1–2 kcal/mol apart are shown. H3O+ is found to be the central unit of a few structures optimized. The ionic hydrogen bond was responsible for the stability of the H9O4+ unit in the large hydrated proton clusters. We also find structures with nascent H5O2+ units at the center whose energy is close to, sometimes even lower than that of the H3O+ centered structures. This can be used to explain the solvation facilitated proton transfer in clusters and in solution. The vibrational frequencies of the structures we optimized are tabulated and compared with the experimental results of Price et al. Questions are raised regarding their prediction of a new feature due to water molecules in the third solvation shell. Some new features have been observed for large clusters with heretofore unpredicted structures.

No abstract

We show that in the mean spherical approximation for a mixture of arbitrary size and charge hard ions in a dipolar solvent all the properties are expressible in terms of three parameters; a screening parameter Γ, a ion-dipole interaction parameter B10, and a dipole–dipole interaction parameter b2, which are given by the solution of a set of algebraic equations. In the case of equal ionic size, the solution is quite simple and very similar to previous results which the size of ion are equal to the size of dipole (σ=σn=1). In the low density and high coupling limits, explicit results are given for the three parameters and for the thermodynamics. The calculations show that the model becomes the primitive model for infinite dilution and vanishingly small solvent molecules.

No abstract

Proteins that interact with DNA play vital roles in all mechanisms of gene expression and regulation. In order to understand these activities, it is crucial to analyze and identify DNA-binding residues on DNA-binding protein surfaces. Here, we proposed two novel features B-factor and packing density in combination with several conventional features to characterize the DNA-binding residues in a well-constructed representative dataset of 119 protein-DNA complexes from the Protein Data Bank (PDB). Based on the selected features, a prediction model for DNA-binding residues was constructed using support vector machine (SVM). The predictor was evaluated using a 5-fold cross validation on above dataset of 123 DNA-binding proteins. Moreover, two independent datasets of 83 DNA-bound protein structures and their corresponding DNA-free forms were compiled. The B-factor and packing density features were statistically analyzed on these 83 pairs of holo-apo proteins structures. Finally, we developed the SVM model to accurately predict DNA-binding residues on protein surface, given the DNA-free structure of a protein. Results showed here indicate that our method represents a significant improvement of previously existing approaches such as DISPLAR. The observation suggests that our method will be useful in studying protein-DNA interactions to guide consequent works such as site-directed mutagenesis and protein-DNA docking.