Probability-based model of protein-protein interactions on biological timescales.

Background: Simulation methods can assist in describing and understanding complex networks of interacting proteins, providing fresh insights into the function and regulation of biological systems. Recent studies have investigated such processes by explicitly modelling the diffusion and interactions of individual molecules. In these approaches, two entities are considered to have interacted if they come within a set cutoff distance of each other.

Developing a move-set for protein model refinement.

Motivation: A wide variety of methods for the construction of an atomic model for a given amino acid sequence are known, the more accurate being those that use experimentally determined structures as templates. However, far fewer methods are aimed at refining these models. The approach presented here carefully blends models created by several different means, in an attempt to combine the good quality regions from each into a final, more refined, model.

Incorporation of flexibility into rigid-body docking: applications in rounds 3-5 of CAPRI.

We have submitted models for all 9 targets in Rounds 3-5 of CAPRI and have predicted at least 30% of the correct contacts for 4 of the targets and at least 10% of the correct contacts for another 4 targets. We have employed a variety of techniques but have had the greatest success by combining established rigid-body docking with a variety of initial conformations generated by molecular dynamics.

Comparative modelling: an essential methodology for protein structure prediction in the post-genomic era.

The gap between the number of protein sequences and protein structures is increasing rapidly, exacerbated by the completion of numerous genome projects now flooding into public databases. To fill this gap, comparative protein modelling is widely considered the most accurate technique for predicting the three-dimensional shape of proteins. High-throughput, automatic protein modelling should considerably increase our access to protein structures other than those determined by experimental techniques such as X-ray crystallography and NMR (nuclear magnetic resonance) spectroscopy.

Novel use of a genetic algorithm for protein structure prediction: searching template and sequence alignment space.

A novel genetic algorithm was applied to all CASP5 targets. The algorithm simultaneously searches template and alignment space. Results show that the current implementation of the method is perhaps most useful in recognizing and refining remote homology targets.

Guided docking: first step to locate potential binding sites.

The long-range electrostatic forces of the targets in round 2 of the Critical Assessment of PRediction of Interactions (CAPRI) experiment were examined and a simple guided docking method, based on these forces, was applied. The method described consists of calculating an initial rigid body trajectory and an optional final, fully flexible refinement stage. Although only limited success was found in predicting the final complexes, some interesting information was discovered.

In silico protein recombination: enhancing template and sequence alignment selection for comparative protein modelling.

Comparative modelling of proteins is a predictive technique to build an atomic model for a given amino acid sequence, on the basis of the structures of other proteins (templates) that have been determined experimentally. Critical problems arise in this procedure: selecting the correct templates, aligning the query sequence with them and building the non-conserved surface loops. In this work, we apply a genetic algorithm, with crossover and mutation, as a new tool to overcome the first two.