Antibody Evolution Constrains Conformational Heterogeneity by Tailoring Protein Dynamics

The evolution of proteins with novel function is thought to start from precursor proteins that are conformationally heterogeneous. The corresponding genes may be duplicated and then mutated to select and optimize a specific conformation. However, testing this idea has been difficult because of the c...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-09, Vol.103 (37), p.13722-13727
Main Authors: Zimmermann, Jörg, Oakman, Erin L., Thorpe, Ian F., Shi, Xinghua, Abbyad, Paul, Brooks, Charles L., Boxer, Steven G., Romesberg, Floyd E.
Format: Article
Language:English
Subjects:
Amplitude
Animals
Antibodies - chemistry
Antibodies - genetics
Binding sites
Biological Sciences
Contrapuntal motion
Crystal structure
Dyes
Evolution
Evolution, Molecular
Flexibility
Fluorescein
Fluorescence
Humans
Immunoglobulin Fab Fragments - chemistry
Immunoglobulin Fab Fragments - genetics
Kinetics
Molecular evolution
Molecules
Monoclonal antibodies
Mutation
Protein Conformation
Proteins
Proteins - chemistry
Proteins - genetics
Spectrum analysis
Surface Plasmon Resonance
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Summary:The evolution of proteins with novel function is thought to start from precursor proteins that are conformationally heterogeneous. The corresponding genes may be duplicated and then mutated to select and optimize a specific conformation. However, testing this idea has been difficult because of the challenge of quantifying protein flexibility and conformational heterogeneity as a function of evolution. Here, we report the characterization of protein heterogeneity and dynamics as a function of evolution for the antifluorescein antibody 4-4-20. Using nonlinear laser spectroscopy, surface plasmon resonance, and molecular dynamics simulations, we demonstrate that evolution localized the Ab-combining site from a heterogeneous ensemble of conformations to a single conformation by introducing mutations that act cooperatively and over significant distances to rigidify the protein. This study demonstrates how protein dynamics may be tailored by evolution and has important implications for our understanding of how novel protein functions are evolved.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0603282103