Gathering Them in to the Fold

tion trials, preferring the shorter The first was held in 19947 (see Gathering sequences which are members of a http://iris4.carb.nist.gov/); the sec sequence family: shorter sequences ond will run throughout 19968 were felt to be easier to predict, and ( CASP2: second meeting for the them in to methods such as secondary struc critical assessment of methods of ture prediction are significantly protein structure prediction, Asilo the fold more accurate when based on a mar, December 1996; URL: multiple sequence alignment than http://iris4.carb.nist.gov/casp2/ or A definition of the state of the art in on a single sequence: one or two http://www.mrc-cpe.cam.ac.uk/casp the prediction of protein folding homologous sequences whisper 21). pattern from amino acid sequence about their three-dimensional What do the 'hard' results of the was the object of the course/work structure; a full multiple alignment past predication competition and shop "Frontiers of protein structure shouts out loud. the 'soft' results of the feelings of prediction" held at the Istituto di Program systems used included the workshop partiCipants say 1 Ricerche di Biologia Molecolare fold recognition methods by Sippl , about the possibilities of meaning (IRBM), outside Rome, on 8-17 Jones2, Barton (unpublished) and ful prediction? Certainly it is worth October 1995 (organized by T. Rost 3; secondary structure predic trying these methods on your target Hubbard & A. Tramontano; see tion by Rost and Sander\ analysis sequence-if you find nothing http://www.mrc-cpe.cam.ac.uk/irbm of correlated mutations by Goebel, quickly you can stop and return to course951). Thirty participants test Sander, Schneider and Valencia\ the bench. But the field has pro ed methods of fold recognition-is prediction of ~-strand pairings by gressed to the point where it can no this sequence likely produce a Hubbard6, and graphical tools for longer be guaranteed that a predic topology similar to a member of a integration of predicted structural tion will be wrong. library of known structures?-and features into a three-dimensional fold prediction-can we predict a model (Leplae, unpublished). fold without reference to any par Some targets seemed easy-per- T.J.P. Hubbard 1, A.M. Lesk2 and ticular known structures? haps spuriously-in that prediction A. Tramontano3 The protein folding problem has programs produced models that 1 Cambridge Centre for Protein posed an intellectual challenge for were consistent with other data; for Engineering, 2Department of two generations since Anfinsen instance, residues known to be in Haematology,University of Cam• showed that amino acid sequence the active site but distant in the bridge Clinical School, UMRC determines protein structure. sequence appeared nearby in three Centre, Hills Road,Cambridge From a practical point of view, pre dimensions. Others were quickly CB2 2QH, UK diction will be needed to keep pace abandoned when no method gave 31stituto di Ricerche di Biologia with the rush of sequence data, espe clear results (detailed reports are Molecolare (IRBM) P. Angeletti, via cially those emerging from whole available at the URL mentioned Pontina, Km 30.600, 00040 genome projects. The pace of above along with analysis of each of Pomezia (Roma), Italy

structure determinations is incr<;:as the 112 targets and descriptions of 1. Sippi, M.J. & Floeckner, H. structure4, 15-19 ing also: typically three structures the methods used). (1996). It is impossible to J'udge predic- 2. Jones, D.T., Taylor, W.R. & Thornton, J.M. are being deposited in the Protein Nature 358, 86-89 (1992). Data Bank per day-that is, every tions until structures are deter- 3. Rest, B. in Proceedings of the Third mined experimentally; conversely, International Conference on Intelligent time you sit down to a meal, some Systems for Molecular Biology, Cambridge, one has deposited a structure! But evaluation of the methods requires UK (eds. Rawlings, C.J. et al.) 314-321 (AAAI applying them before an experi- Press, Menlo Park, CA, USA, 1995). no one could keep pace with the 4. Rest, B. & Sander, C. J. Mol. Bioi. 232, sequencers. mental structure is revealed. Such 584-599 (1993). 'bl' d t t ' r organ!' zed as protein 5. Gobel, u., Sander, c., Schneider, R. & The raw material for the work m es S a e Valencia, A. Proteins 18,309-317 (1994). shop was assembled by open invita structure prediction competitions 6. Hubbard, T.J. in Proceedings of the h h biotechnology computing track, protein tion to biologists to submit (starte d b Y J0 h n M ou It ) , W ere t e structure prediction minitrack of the 27th sequences of unknown structure: challenge is to submit predicted HICSS (eds. Lathrop, R.H.) 336-354 (IEEE structures before a deadline, after Computer Society Press, 1994). (see also 112 were received, and those http://www.mrc-cpe.cam.ac.uk!th/papers) homologous to known structures which the crystallographic results 7. Moult, J., Judson, R., Fidel is, K., & Pedersen, are revealed-to the delight of J.T. Proteins Struct. Funct. Genet. 23 3, ii-iv were excluded. Groups at the work (1995). shop selected 17 targets for predic- some and the chagrin of others. 8. Nature Struct. Biology3, 209-210 (1996).

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