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Kinetic and affinity predictions of a protein-protein interaction using multivariate experimental design
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2002 In: Journal of Biological Chemistry, Vol. 277, no 33, 29897-29907 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2002. Vol. 277, no 33, 29897-29907 p.
Identifiers
URN: urn:nbn:se:uu:diva-91948OAI: oai:DiVA.org:uu-91948DiVA: diva2:164845
Available from: 2004-06-02 Created: 2004-06-02Bibliographically approved
In thesis
1. Characterization of Biomolecular Interactions Using a Multivariate Approach
Open this publication in new window or tab >>Characterization of Biomolecular Interactions Using a Multivariate Approach
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents a novel bioinformatic methodology denoted the bio-chemometric approach. The methodology is designed for generation of detailed descriptions and predictions of biomolecular interactions. It is based on multivariate analysis of the sensitivity of a biomolecular interaction to multiple minor changes in the experimental conditions. In this work, either the chemical environment where the interaction takes place, or the molecular structure of one of the interacting molecules, was varied. The sensitivity of the interaction to the performed variations was presented as a vector called the sensitivity fingerprint. The bio-chemometric approach was tested on several biomolecular interactions. Useful descriptions of the interactions were obtained by measuring binding kinetics for each interaction in 12-20 different buffers and correlating buffer composition to binding kinetics. The obtained chemical sensitivity fingerprints were reproducible, significantly different and showed a weak correlation to binding site properties for the tested interactions. The results indicate that the fingerprints contained useful information about the binding site. The predictive ability of the bio-chemometric approach was tested on two different biomolecular interactions where one of the binding partners was slightly modified into multiple analogues by amino acid exchanges. In one example, interactions of 18 peptide analogues with an antibody gave data that could be used for accurate prediction of the dissociation rates of novel analogues. Reliable predictions of binding kinetics and affinity were also obtained for single domain camel antibody analogues binding to a protein antigen. By using the three-dimensional structure of camel antibodies and data obtained using the bio-chemometric approach, even the importance of non-exchanged amino acids for the binding could be estimated. The bio-chemometric approach can potentially improve the development of peptides and proteins for therapeutic and diagnostic use. It is suggested to be valid for general use in biochemistry.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 60 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1363
Keyword
Biochemistry, Chemometrics, QSAR, Interaction, kinetics, Biokemi
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-4322 (URN)91-554-5999-4 (ISBN)
Public defence
2004-09-18, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskölds väg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-06-02 Created: 2004-06-02Bibliographically approved

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