BiGGER
BiGGER stands for Bimolecular complex Generation with Global Evaluation and Ranking. The relevant publications on this work are:
Krippahl, L., Moura, J.J., Palma, P.N., Modeling Protein Complexes with BiGGER (2003). Proteins. 2003 Jul 1;52(1):19-23. Download .pdf
Palma, P.N., Krippahl, L.,Wampler, J.W., Moura, J.G., A New (Soft)Docking Algorithm for Predicting Protein Interactions. Protein:Struc. Func. Gen. 2000 Jun 1;39(4):372-84.
Grid Representation
BiGGER represents protein structures using three-dimensional grids with a typical resolution o 1A per grid cell. Surface and core grids distinguish realistic placements, where surface cells overlap, from unlikely configurations where core grid cells overlap. Constraint programming techniques are used to prune the translational search space, which covers all relevant relative positions of the two grid sets.
Filtering and Ranking
BiGGER retains a few thousand of the best models from the billions of possibilities searched. These best models are those with the highest surface grid overlaps, optionally filtered to rule out unfavourable side chain or electrostatic interactions. This set is then evaluated in more detail and ranked according to an aggregate value of geometry, side chain contacts, solvent exclusion effects and electrostatic interactions.
Constraining the Search Space
Constraint propagation can be used to prune the search based on experimental data. A generic constraint allows the user to specify a minimum number of interface contacts from a set of possible contacts. This can model noisy data, such as site-directed mutagenesis results. A number of mutations affect the formation of the complex, but not all residues are necessarily at the interface. This uncertainty can be modelled by providing BiGGER with all the sites that affect complex formation and constraining the search to keep a minimum number of those at the interface, without having to specify which.
Applications
BiGGER has been used to model several biochemical systems. Here are a few recent publications that illustrate the possibilities of BiGGER.
Monaco S, Gioia M, Rodriguez J, Fasciglione GF, Di Pierro D, Lupidi G, Krippahl L, Marini S, Coletta M., (2007), Modulation of the proteolytic activity of matrix metalloproteinase-2 (gelatinase A) on fibrinogen. Biochem J. 2007 Mar 15;402(3):503-13.
Krippahl L, Palma PN, Moura I., Moura JG. Modelling the Electron-Transfer Complex Between Aldehyde Oxidoreductase and Flavodoxin (2006). Eur. J. of Inor. Chem., in press
Palma PN, Lagoutte B, Krippahl L, Moura JJ, Guerlesquin F. Synechocystis ferredoxin / ferredoxin - NADP(+)-reductase/NADP+ complex: Structural model obtained by NMR-restrained docking. (2005) FEBS Lett. 2005 Aug 29;579(21):4585-90.
Impagliazzo A, Krippahl L and Ubbink M. Pseudoazurin : Nitrite Reductase Interactions (2005) ChemBioChem 6, 1648-1653 Download .pdf