A decade of CASP: progress, bottlenecks and prognosis in protein structure prediction

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For the past ten years, CASP (Critical Assessment of Structure Prediction) has monitored the state of the art in modeling protein structure from sequence. During this period, there has been substantial progress in both comparative modeling of structure (using information from an evolutionarily related structural template) and template-free modeling. The quality of comparative models depends on the closeness of the evolutionary relationship on which they are based. Template-free modeling, although still very approximate, now produces topologically near correct models for some small proteins. Current major challenges are refining comparative models so that they match experimental accuracy, obtaining accurate sequence alignments for models based on remote evolutionary relationships, and extending template-free modeling methods so that they produce more accurate models, handle parts of comparative models not available from a template and deal with larger structures.

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

References (35)

  • Kahsay RY, Wang G, Gao G, Liao L, Dunbrack R: Quasi-consensus based comparison of profile hidden Markov models for...
  • J. Skolnick et al.

    TOUCHSTONE: a unified approach to protein structure prediction

    Proteins

    (2003)
  • P.E. Bourne

    CASP and CAFASP experiments and their findings

    Methods Biochem Anal

    (2003)
  • A. Zemla et al.

    Processing and evaluation of predictions in CASP4

    Proteins

    (2001)
  • A. Tramontano et al.

    Assessment of homology-based predictions in CASP5

    Proteins

    (2003)
  • L.N. Kinch et al.

    CASP5 assessment of fold recognition target predictions

    Proteins

    (2003)
  • P. Aloy et al.

    Predictions without templates: new folds, secondary structure, and contacts in CASP5

    Proteins

    (2003)
  • C. Venclovas et al.

    Assessment of progress over the CASP experiments

    Proteins

    (2003)
  • S.Y. Chung et al.

    The use of side-chain packing methods in modeling bacteriophage repressor and cro proteins

    Protein Sci

    (1995)
  • S. An et al.

    Trans-editing of Cys-tRNAPro by Haemophilus influenzae YbaK protein

    J Biol Chem

    (2004)
  • C. DeWeese-Scott et al.

    Molecular modeling of protein function regions

    Proteins

    (2004)
  • S.F. Altschul et al.

    Gapped BLAST and PSI-BLAST: a new generation of protein database search programs

    Nucleic Acids Res

    (1997)
  • K. Karplus et al.

    Evaluation of protein multiple alignments by SAM-T99 using the BAliBASE multiple alignment test set

    Bioinformatics

    (2001)
  • K. Karplus et al.

    Hidden Markov models for detecting remote protein homologies

    Bioinformatics

    (1998)
  • T. Ohlson et al.

    Profile-profile methods provide improved fold-recognition: a study of different profile-profile alignment methods

    Proteins

    (2004)
  • G. Wang et al.

    Scoring profile-to-profile sequence alignments

    Protein Sci

    (2004)
  • B. Wallner et al.

    Using evolutionary information for the query and target improves fold recognition

    Proteins

    (2004)
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