Rebecca C. Wade

Biomolecular diffusional association.

The primary method for the computational study of biomolecular diffusional association is Brownian dynamics. Recent work has seen advances in the efficiency of computing association rates and in the accuracy of simulation models. New areas to which Brownian dynamics has been applied include protein polymerisation and protein adsorption to a surface. There has recently been particularly intense study of protein-protein association, and Brownian dynamics, together with other theoretical and experimental approaches, has led to new insights into the determinants of protein-protein binding kinetics.

Electrostatic Analysis and Brownian Dynamics Simulation of the Association of Plastocyanin and Cytochrome F

The oxidation of cytochrome f by the soluble cupredoxin plastocyanin is a central reaction in the photosynthetic electron transfer chain of all oxygenic organisms. Here, two different computational approaches are used to gain new insights into the role of molecular recognition and protein-protein association processes in this redox reaction. First, a comparative analysis of the computed molecular electrostatic potentials of seven single and multiple point mutants of spinach plastocyanin (D42N, E43K, E43N, E43Q/D44N, E59K/E60Q, E59K/E60Q/E43N, Q88E) and the wt protein was carried out. The experimentally determined relative rates (k(2)) for the set of plastocyanin mutants are found to correlate well (r(2) = 0.90 - 0.97) with the computed measure of the similarity of the plastocyanin electrostatic potentials. Second, the effects on the plastocyanin/cytochrome f association rate of these mutations in the plastocyanin eastern site were evaluated by simulating the association of the wild type and mutant plastocyanins with cytochrome f by Brownian dynamics. Good agreement between the computed and experimental relative rates (k(2)) (r(2) = 0.89 - 0.92) was achieved for the plastocyanin mutants. The results obtained by applying both computational techniques provide support for the fundamental role of the acidic residues at the plastocyanin eastern site in the association with cytochrome f and in the overall electron-transfer process.

‘Flu’ and structure-based drug design

The threat of a catastrophic outbreak of influenza is ever present. Vaccines are only partially effective and the two compounds, amantidine and rimantidine, used clinically against influenza A cause side-effects and rapid viral resistance. Recent advances bring hope that specific and potent drugs against influenza may soon be available in the clinic. These compounds were designed to inhibit influenza neuraminidase (NA), one of the viral coat glycoproteins, using the crystal structure of NA which was first published in 1983. In this review, the application of structure-based drug design approaches to the design of anti-influenza agents targeted at NA and haemagglutinin (HA), the other viral surface glycoprotein, is discussed.

Towards molecular dynamics simulation of large proteins with a hydration shell at constant pressure

Molecular dynamics simulation of a large protein in explicit water with periodic boundary conditions is extremely demanding in terms of computation time. Consequently, we have sought approximations of the solvent environment that model its important features. Here, we describe our SAPHYR (Shell Approximation for Protein HYdRation) model in which the protein is surrounded by a shell of water molecules maintained at constant pressure. In addition to the usual pairwise interatomic interactions, these water molecules are subjected to forces approximating van der Waals and dipole-dipole interactions with the implicit surrounding bulk solvent. The SAPHYR model is tested for a system of one argon atom in water and for the protein ubiquitin, and then applied to cytochrome P450cam, a protein with over 400 residues. The results demonstrate that structural and dynamic properties of the simulated systems are improved by use of the SAPHYR model, and that this model provides a significant computational saving over simulations with periodic boundary conditions.

MolSurfer: two-dimensional maps for navigating three-dimensional structures of proteins.

3xMadura, J.D. et al. Comp. Phys. Comm. 1995; 91: 57–95CrossRef | Scopus (506)See all References3

CASP2 Molecular Docking Predictions With the LIGIN Software

Seven docking predictions were made with the LIGIN program. In six cases the location of the binding pocket was identified correctly by systematically docking everywhere within the protein structure. In two cases the ligand was docked to within 1.8 Å RMSD of the experimentally determined structure. LIGIN has not been optimized to deal with highly flexible ligands that dock at the surface of proteins. Consequently, in three cases the exposed part of the ligand was docked poorly, although the buried parts were docked well, and made similar atomic contacts with the protein as in the experimentally determined structure. Proteins, Suppl. 1:210–214, 1997.

Biologically Relevant Properties of Copper-Containing Proteins Analyzed by Means of Semiquantitative and Quantitative Theoretical Descriptors

Acquiring insights into the mechanisms governing biological activity and, in general, molecular recognition has important consequences because it can result in improved techniques for designing new drugs and engineering proteins with desired properties and functions in a specific environment.

Combine and Free-Wilson QSAR Analysis of Nuclear Receptor-DNA Binding

Specific binding of transcription factors to DNA is crucial for gene regulation. We have studied the specificity of binding of transcription factors from the nuclear receptor family to DNA using two QSAR methods: a) a Free-Wilson like method and b) Comparative Binding Energy (COMBINE)1 analysis.