Modelling zinc-binding proteins with GADGET: genetic algorithm and distance geometry for exploring topology.
A novel combination of optimization methods (Genetic Algorithm with Distance Geometry) has been developed and shown to find near-optimal solutions to a set of imposed structural constraints. With this modelling tool (GADGET), the fold-space of a variety of small zinc-binding proteins was investigated under the constraints required to form a zinc-binding site (or pair of sites). Analysis of the results concentrated on the ring-finger domain as the "classic" zinc-finger domains were too constrained to provide much topological variety, whilst the TFIIH domain (which has large unstructured loops) did not behave well. The intermediate ring-finger domain, however, was found to adopt a variety of different folds, many of which had near-optimal scores under the fitness function employed in GADGET (forming good secondary structures and zinc-coordination). Although the native fold was dominant amongst the solutions, the discovery of good alternate folds shows that even the eight residues constrained to form two zinc-binding sites was not sufficient to uniquely determine the native fold. Despite this, the fold-space of 48 theoretically possible folds was greatly reduced with just six topologies found in significant numbers.
Petersen
Kjell
K
Department of Informatics, University of Bergen, PB7800, N-5020 Bergen, Norway.
Taylor
William R
WR
D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009010:Monte Carlo Method; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism*; D016335:Zinc Fingers
D002352:Carrier Proteins; D011506:Proteins; C017800:zinc-binding protein; D015032:Zinc