From Protein Structure to Function with Bioinformatics.pdf

Chapter 2Fold RecognitionLawrence A. KelleyAbstract Fold recognition is concerned with the prediction of protein threedimensionalstructure from amino sequence by the detection of extremely remotehomologous or analogous relationships to known structures. As such it lies midwaybetween ab initio protein folding and close homology modelling. This chaptersurveys both the history of the field and the current state-of-the art, from threadingand sequence profile matching to modern meta-server consensus approaches andhomology network analysis.2.1 IntroductionThe amino acid sequence of a protein determines its structure, which in turn determinesits biological function and mechanism of action. Protein folding is the bridgebetween the instructions for living things and the living thing itself. This key paradigmin biochemistry accounts for nearly one in four Nobel Prizes in Chemistrysince 1956 (Seringhaus and Gerstein 2007). In 2005 Science named the proteinfolding problem one of the 125 biggest unsolved problems in science (ScienceEditorial 2005).At the time of writing, over 5.8 million unique protein sequences have beenfound in the hundreds of genomes that have been sequenced. This number has beenexponentially growing for two decades now, and is set to grow even faster. The newmeta-genomics projects involving shotgun-sequencing random samples of seawateraround the globe every 200 miles are finding 1.3 million new genes and as many as50,000 new species in each barrel of seawater. Single sequencing machines cannow sequence 100 million base pairs in 24 h and this speed is set to increase andthe price set to drop.Meanwhile, despite the progress of the high-throughput structural genomicsinitiatives and the large arrays of NMR and crystallography robots working 24 ha day to determine protein structure, only 50,000 protein structures have so farbeen solved.L.A. KelleyStructural Bioinformatics Group, Department of Biological Sciences,Imperial College London, SW7 2AY, UKe-mail: l.a.kelley@ic.ac.ukD.J. Rigden (ed.) From Protein Structure to Function with Bioinformatics, 27© Springer Science + Business Media B.V. 2009