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Bruce Tidor and Roger D. Kamm. Zyto, Aurore Massachusetts Institute of Technology. Biological Engineering Division. Massachusetts Institute of Technology. Department of Biological Engineering 2009-04-29T17:08:22Z 2009-04-29T17:08:22Z 2008 2008 http://hdl.handle.net/1721.1/45207 301815874 Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2008. Includes bibliographical references (leaves 100-112). 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. by Aurore Zyto. Ph.D. 112 leaves eng Massachusetts Institute of Technology MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. http://dspace.mit.edu/handle/1721.1/7582 Biological Engineering Division. Computational modeling of protein-biomolecule interactions with application to mechanotransduction and antibody maturation Thesis application/pdf false Publication unknown unknown <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="dcc87c07-5e3b-476b-8e5e-2f77bd7afb5d"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Language>eng</Language> <Title>Computational modeling of protein-biomolecule interactions with application to mechanotransduction and antibody maturation</Title> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2008</PublicationDate> <Authors> <Author> <DisplayName>Zyto, Aurore</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Massachusetts Institute of Technology</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>http://dspace.mit.edu/handle/1721.1/7582</License> <Keyword>Biological Engineering Division.</Keyword> <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.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>