Modeling the anti-CEA antibody combining site by homology and conformational search

Authors

  • Maria T. Mas,

    1. Physical Biochemistry Section, Division of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010
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  • Kenneth C. Smith,

    1. Department of Biology, Columbia University, New York, New York 10027
    Current affiliation:
    1. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032
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  • David L. Yarmush,

    1. Department of Biology, Columbia University, New York, New York 10027
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  • Kazuo Aisaka,

    1. Physical Biochemistry Section, Division of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010
    Current affiliation:
    1. Kyowa Hakko Kogyo Company, Ltd., Tokyo Research Laboratories, 3-6-6 Asahimachi, Machidashi, Tokyo, Japan
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  • Richard M. Fine

    Corresponding author
    1. Department of Biology, Columbia University, New York, New York 10027
    Current affiliation:
    1. Biosym Technologies Inc., 4 Century Dr., Parsippany, NJ 07054
    • Biosym Technologies Inc., 4 Century Dr., Parsippany, NJ 07054
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Abstract

A model for an antibody specific for the carcinoembryonic antigen (CEA) has been constructed using a method which combines the concept of canonical structure with conformational search. A conformational search technique is introduced which couples random generation of backbone loop conformations to a simulated annealing method for assigning side chain conformations. This technique was used both to verify conformations selected from the set of known canonical structures and to explore conformations available at the H3 loop in CEA ab initio. Canonical structures are not available for H3 due to its variability in length, sequence, and observed conformation in known antibody structures Analysis of the results of conformational search resulted in three equally probable conformations for H3 loop in CEA. Force field energies, solvation free energies, exposure of charged residues and burial of hydrophobic residues, and packing of hydrophobic residues at the base of the loop were used as selection criteria. The existence of three equally plausible structures may reflect the high degree of flexibility expected for an exposed loop of this length. The nature of the combining site and features which could be important to interaction with antigen are discussed. © 1992 Wiley-Liss, Inc.

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