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Computational modeling of protein-biomolecule interactions with application to mechanotransduction and antibody maturation

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dc.contributor.advisor Bruce Tidor and Roger D. Kamm. en_US Zyto, Aurore en_US
dc.contributor.other Massachusetts Institute of Technology. Biological Engineering Division. en_US 2009-04-29T17:08:22Z 2009-04-29T17:08:22Z 2008 en_US 2008 en_US
dc.description Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2008. en_US
dc.description Includes bibliographical references (leaves 100-112). en_US
dc.description.abstract Cell survival, growth, differentiation, migration, and communication all depend on the appropriate combination of specific interactions between proteins and biomolecules. Therefore, understanding the molecular mechanisms influencing protein-biomolecule binding interactions is important both for fundamental knowledge and as a foundation for therapeutic applications and biotechnology. This thesis presents two applications of computational modeling to study protein-biomolecule binding in different contexts. First, we sought to characterize effects of applied mechanical force on protein structural and biochemical properties. Despite growing experimental evidence of force-regulated cell behavior, the molecular mechanisms involved in force sensing and transmission are still largely unknown. We adapted a free energy method to directly compute the change in binding affinity upon force application. Our simulations demonstrated that differential responses in the bound and unbound state of a protein-ligand complex can lead to graded force-modulation of binding affinity. Application to a prototypical protein system - the helical bundle complex of a paxillin fragment bound to the FAT domain of focal adhesion kinase (FAK) revealed several structural mechanisms responsible. Second, we used computational methods to design individual mutations computed to improve binding affinity of an antibody-small molecule complex with relevance to cancer treatment. Our calculations suggested several beneficial mutations for experimental characterization. The work illustrates the value of computational modeling for understanding protein-biomolecule interactions with application to therapeutic development and advances in biotechnology. en_US
dc.description.statementofresponsibility by Aurore Zyto. en_US
dc.format.extent 112 leaves en_US
dc.language.iso eng en_US
dc.publisher Massachusetts Institute of Technology en_US
dc.rights M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. en_US
dc.rights.uri en_US
dc.subject Biological Engineering Division. en_US
dc.title Computational modeling of protein-biomolecule interactions with application to mechanotransduction and antibody maturation en_US
dc.type Thesis en_US Ph.D. en_US
dc.contributor.department Massachusetts Institute of Technology. Biological Engineering Division. en_US
dc.identifier.oclc 301815874 en_US

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