A critical assessment of comparative molecular modeling of tertiary structures of proteins*

Authors

  • Steven Mosimann,

    1. Medical Research Council of Canada, Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
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  • Ron Meleshko,

    1. Medical Research Council of Canada, Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
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  • Michael N. G. James

    Corresponding author
    1. Medical Research Council of Canada, Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
    • Medical Research Council of Canada, Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
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  • *

    This assessment does not indicate that anyone particular modeling group or modeling technique is superior to any other. We do not believe that comparative molecular models can be ranked using a single or even several numeric indicators. As such, claims that particular modeling techniques are superior based upon the results herein are not justifiable, in our opinion.

Abstract

In spite of the tremendous increase in the rate at which protein structures are being determined, there is still an enormous gap between the numbers of known DNA-derived sequences and the numbers of three-dimensional structures. In order to shed light on the biological functions of the molecules, researchers often resort to comparative molecular modeling. Earlier work has shown that when the sequence alignment is in error, then the comparative model is guaranteed to be wrong. In addition, loops, the sites of insertions and deletions in families of homologous proteins, are exceedingly difficult to model. Thus, many of the current problems in comparative molecular modeling are minor versions of the global protein folding problem. In order to assess objectively the current state of comparative molecular modeling, 13 groups submitted blind predictions of seven different proteins of undisclosed tertiary structure. This assessment shows that where sequence identity between the target and the template structure is high (> 70%), comparative molecular modeling is highly successful. On the other hand, automated modeling techniques and sophisticated energy minimization methods fail to improve upon the starting structures when the sequence identity is low (∼30%). Based on these results it appears that insertions and deletions are still major problems. Successfully deducing the correct sequence alignment when the local similarity is low is still difficult. We suggest some minimal testing of submitted coordinates that should be required of authors before papers on comparative molecular modeling are accepted for publication in journals. © 1995 Wiley-Liss, Inc.

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