title: Comparative protein structure modeling by iterative alignment, model building and model assessment.
abstract: 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(alpha) atoms of the model that were within 5 A of the corresponding C(alpha) 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.
authors.affiliation: Laboratory of Molecular Biophysics, Pels Family Center for Biochemistry and Structural Biology, The Rockefeller University, New York, NY 10021, USA.
authors.forename: Bino
authors.initials: B
authors.lastname: John
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
mesh_terms: D000465:Algorithms; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D015203:Reproducibility of Results; D016415:Sequence Alignment / Q000379:methods
chemical_list: D011506:Proteins