Nucleic Acids Research, 2003, Vol. 31, No. 14 3982-3992
© 2003 Oxford University Press
Comparative protein structure modeling by iterative alignment, model building and model assessment
Laboratory of Molecular Biophysics, Pels Family Center for Biochemistry and Structural Biology, The Rockefeller University, New York, NY 10021, USA and 1 Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry and California Institute for Quantitative Biomedical Research, University of California at San Francisco, San Francisco, CA 94143, USA
*To whom correspondence should be addressed at Mission Bay Genentech Hall, Suite N472D, 600 16th Street, University of California at San Francisco, San Francisco, CA 94143-2240, USA. Tel: +1 415 514 4227; Fax: +1 415 514 4231; Email: sali{at}salilab.org
Comparative or homology protein structure modeling is severely limited by errors in the alignment of a modeled sequence with related proteins of known three-dimensional structure. To ameliorate this problem, we have developed an automated method that optimizes both the alignment and the model implied by it. This task is achieved by a genetic algorithm protocol that starts with a set of initial alignments and then iterates through re-alignment, model building and model assessment to optimize a model assessment score. During this iterative process: (i) new alignments are constructed by application of a number of operators, such as alignment mutations and cross-overs; (ii) comparative models corresponding to these alignments are built by satisfaction of spatial restraints, as implemented in our program MODELLER; (iii) the models are assessed by a variety of criteria, partly depending on an atomic statistical potential. When testing the procedure on a very difficult set of 19 modeling targets sharing only 4–27% sequence identity with their template structures, the average final alignment accuracy increased from 37 to 45% relative to the initial alignment (the alignment accuracy was measured as the percentage of positions in the tested alignment that were identical to the reference structure-based alignment). Correspondingly, the average model accuracy increased from 43 to 54% (the model accuracy was measured as the percentage of the C
atoms of the model that were within 5 Å of the corresponding C atoms in the superposed native structure). The present method also compares favorably with two of the most successful previously described methods, PSI-BLAST and SAM. The accuracy of the final models would be increased further if a better method for ranking of the models were available.
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