Patrice Koehl (University of California, Davis)
Michael Levitt (Stanford University)
Marc Delarue (Institut Pasteur, Paris, France)
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Patrice Koehl (University of California, Davis) Michael Levitt (Stanford University) Marc Delarue (Institut Pasteur, Paris, France) |
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Why Do We Need Comparative Protein Structure Modelling ?It has been hypothesized that the total number of different protein folds is finite, and roughly of the order of 1000. The fact that the protein structure space is finite, and much smaller than the protein sequence space has given rise to the hope that it is possible to have representative structure models for all protein sequences, without going into the expensive procedures of systematic experimental structure determination. Structural genomics is currently focusing on the construction of an extensive library of folds, and a figure of 10,000 to 100,000 representative proteins has been proposed. With such a library, it is expected that models for all proteins can be constructed.
The success of this approach is, however,
strongly correlated to our ability to identify a proper structural template
for a protein of interest, and to build an accurate motel for this protein,
based on the template. Techniques to solve the identification step, or
"fold recognition" problem rely on the assumption that similarities between
the sequences of two proteins imply similarities between the structures
of these proteins. The building step is usually referred to "homology modelling",
or "comparative protein structure modelling". ProModel was designed as
a method for solving this problem, and is described in details below.
What is Comparative Protein Structure Modelling?Comparative protein structure modeling usually proceeds in 4 steps:
What is ProModel, and how does it work ?
Many problems in computational biology face large combinatorial obstacles that cannot be solved exhaustively. The self consistent mean field theory or SCMF provides an efficient, fast and robust method to alleviate these obstacles. A genneral description of this theory applied to protein modelling is available here. The simplest homology modelling case occurs when there are no gaps in the alignment of the sequences of the template and target protein, in which case the framework consists of a complete backbone. Building a structural model for the target protein is then reduced to predicting the conformation of the sidechains of the protein. A solution to this problem based on the SCMF theory is described here. In general, the framework used as a starting point for comparative protein structure modelling consists of fragments of protein backbone, separated by gaps. One of the first step in the modelling process is to generate possible protein fragment conformations in order to fill in these gaps. A brief description of the method used in ProModel to solve this problem, as well as references to other existing techniques is available here. ProModel combines all tools described above in a general program designed to select protein fragments for filling the gaps in the framework and simulataneously precit the conformation of all sidechains of the protein. A general overview of ProModel is available here. Useful linksProModel is one among many programs written for solving
the comparative protein structure moedlling program. We provide links to
other available programs and/or web services. This list is by no means
exhaustive.
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