A decade of CASP: progress, bottlenecks and prognosis in protein structure prediction
Introduction
This article reviews progress in modeling protein structure from amino acid sequence over the past ten years, as monitored by CASP (Critical Assessment of Structure Prediction); another independent useful review is [1•]. CASP is a community-wide experiment with the primary aim of assessing the effectiveness of modeling methods. This review covers CASP experiments 1 (held in 1994) through 6 (2004). The emphasis is on what has been learnt about the strengths and weaknesses of prediction methods, what progress has been made, where there are serious bottlenecks to further progress and how these may eventually be removed. Reviews and reports on the CASP6 experiment were not yet available at the time of writing. Readers are advised to check the literature for newer material.
Section snippets
The CASP experiment
CASP is a large-scale community experiment, conducted every two years. The key feature is that participants make bona fide blind predictions of structures. Over 200 prediction teams from 24 countries participated in CASP6. Information about soon-to-be experimentally determined protein structures is collected and passed on to registered predictors. Over 30 000 predictions for 64 protein targets divided into 90 domains were collected and evaluated. Predictors fall into two categories: teams of
Classes of structure prediction difficulty
Early work in the structure modeling field primarily focused on understanding the nature of the natural folding process and on the development of physics-based force fields to determine the relative free energy of any conformation of a polypeptide chain. These methods were much in evidence at the first CASP, but have largely been supplanted by more successful ‘knowledge-based’ approaches, which utilize the large and rapidly growing number of experimentally determined structures and sequences in
Major current challenges
As detailed above, overcoming four of the current major bottlenecks — close evolutionary relationship models approaching experimental accuracy, improved alignments, refinement of remote evolutionary relationship models and reliable discrimination among possible template-free models — is dependent on the development of effective all-atom structure refinement procedures. The ‘refinement’ problem has received increasing attention in recent years (//www.nigms.nih.gov/psi/reports/comparative_modeling.html
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
CASP is made possible by the participation of the prediction community, the generosity of the experimental community in making new structural information available, and the work of the assessment teams and the organizers. Details are available on the CASP web site (predictioncenter.llnl.gov). We are grateful to the organizers of the CAFASP (Critical Assessment of Fully Automated Structure Prediction) experiments for their cooperation in collecting server predictions. CASP has been supported by
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