{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/72404"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/72404","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Computational Studies on the Mechanical Properties of Muscle and Blood Clot Elasticity","abstract":"Mechanical proteins perform a vital role in cells by transmitting and bearing mechanical forces involved in cell growth, locomotion, and adhesion. Little is known at the molecular level that explains how such proteins are capable of reversibly stretching, in some cases to twice their resting length, upon mechanical tension. In this thesis, MD simulations are employed to study the molecular basis of elasticity for muscle from the protein titin and for blood clots from the protein fibrinogen. These investigations utilize free dynamics MD to verify experimentally observed conformations of proteins, SMD to probe their response to mechanical forces, and adaptive biasing force (ABF) simulations to measure the free energy landscape of tertiary structure transformations. Several domains of titin are investigated in detail: the Z1Z2 domains bound to the protein telethonin at one end of the long protein chain in a relatively immobile region of the muscle fiber, and the I91 domain and 6-Ig tandem 165-70 located at titin's flexible I-band. SMD simulations of the Z1Z2-telethonin complex reveal that telethonin likely functions as an anchor that tightly tethers titin to one end of the muscle fiber so that titin has a stable base to stretch from. ABF simulations of the Z1Z2 and 165-70 domains suggest strongly that the connected domains function as a large entropic spring when stretched from a loose chain to a tight chain but without unfolding individual domains, an example of so-called tertiary structure elasticity. Finally, SMD simulations of the I91 domain were performed to address the timescale disparity between simulations and experiments, demonstrating that even fast simulations capture faithfully protein rupture events. SMD simulations on the blood clot protein fibrinogen reveal that the source of elasticity observed for blood clots arises from a set of intertwined helices that form the core region of the protein. Upon mechanical tension, fibrinogen's coiled-coils unfold according to helical density, rupturing in the order of double helix, triple helix, and finally quadruple helix. All together, these studies on titin and fibrinogen shed light on the how different protein architectures behave as molecular springs.","abstract_html":"Mechanical proteins perform a vital role in cells by transmitting and bearing mechanical forces involved in cell growth, locomotion, and adhesion. Little is known at the molecular level that explains how such proteins are capable of reversibly stretching, in some cases to twice their resting length, upon mechanical tension. In this thesis, MD simulations are employed to study the molecular basis of elasticity for muscle from the protein titin and for blood clots from the protein fibrinogen. These investigations utilize free dynamics MD to verify experimentally observed conformations of proteins, SMD to probe their response to mechanical forces, and adaptive biasing force (ABF) simulations to measure the free energy landscape of tertiary structure transformations. Several domains of titin are investigated in detail: the Z1Z2 domains bound to the protein telethonin at one end of the long protein chain in a relatively immobile region of the muscle fiber, and the I91 domain and 6-Ig tandem 165-70 located at titin's flexible I-band. SMD simulations of the Z1Z2-telethonin complex reveal that telethonin likely functions as an anchor that tightly tethers titin to one end of the muscle fiber so that titin has a stable base to stretch from. ABF simulations of the Z1Z2 and 165-70 domains suggest strongly that the connected domains function as a large entropic spring when stretched from a loose chain to a tight chain but without unfolding individual domains, an example of so-called tertiary structure elasticity. Finally, SMD simulations of the I91 domain were performed to address the timescale disparity between simulations and experiments, demonstrating that even fast simulations capture faithfully protein rupture events. SMD simulations on the blood clot protein fibrinogen reveal that the source of elasticity observed for blood clots arises from a set of intertwined helices that form the core region of the protein. Upon mechanical tension, fibrinogen's coiled-coils unfold according to helical density, rupturing in the order of double helix, triple helix, and finally quadruple helix. All together, these studies on titin and fibrinogen shed light on the how different protein architectures behave as molecular springs.","abstract_has_math":false,"creators":["Lee, Eric Ho-Yin"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Biophysics and Computational Biology","degree_department":null,"school":null,"contributors":["Schulten, Klaus J."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-12-17T22:22:49Z","date_published":"2014-12-17T22:22:49Z","updated_at":"2026-07-22T22:26:06Z","subjects":["Physics, Molecular","Biophysics, Medical","Biophysics, General"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["(UMI)AAI3395582"],"render_values":[{"text":"(UMI)AAI3395582","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2142/72404","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Schulten, Klaus J."]},{"key":"dc:creator","label":"Author","values":["Lee, Eric Ho-Yin"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2014-12-17T22:22:49Z","10000-01-01","2009"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biophysics and Computational Biology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Physics, Molecular","Biophysics, Medical","Biophysics, General"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/72404","(UMI)AAI3395582"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Mechanical proteins perform a vital role in cells by transmitting and bearing mechanical forces involved in cell growth, locomotion, and adhesion. Little is known at the molecular level that explains how such proteins are capable of reversibly stretching, in some cases to twice their resting length, upon mechanical tension. In this thesis, MD simulations are employed to study the molecular basis of elasticity for muscle from the protein titin and for blood clots from the protein fibrinogen. These investigations utilize free dynamics MD to verify experimentally observed conformations of proteins, SMD to probe their response to mechanical forces, and adaptive biasing force (ABF) simulations to measure the free energy landscape of tertiary structure transformations. Several domains of titin are investigated in detail: the Z1Z2 domains bound to the protein telethonin at one end of the long protein chain in a relatively immobile region of the muscle fiber, and the I91 domain and 6-Ig tandem 165-70 located at titin's flexible I-band. SMD simulations of the Z1Z2-telethonin complex reveal that telethonin likely functions as an anchor that tightly tethers titin to one end of the muscle fiber so that titin has a stable base to stretch from. ABF simulations of the Z1Z2 and 165-70 domains suggest strongly that the connected domains function as a large entropic spring when stretched from a loose chain to a tight chain but without unfolding individual domains, an example of so-called tertiary structure elasticity. Finally, SMD simulations of the I91 domain were performed to address the timescale disparity between simulations and experiments, demonstrating that even fast simulations capture faithfully protein rupture events. SMD simulations on the blood clot protein fibrinogen reveal that the source of elasticity observed for blood clots arises from a set of intertwined helices that form the core region of the protein. Upon mechanical tension, fibrinogen's coiled-coils unfold according to helical density, rupturing in the order of double helix, triple helix, and finally quadruple helix. All together, these studies on titin and fibrinogen shed light on the how different protein architectures behave as molecular springs.","Made available in DSpace on 2014-12-17T22:22:49Z (GMT). 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Little is known at the molecular level that explains how such proteins are capable of reversibly stretching, in some cases to twice their resting length, upon mechanical tension. In this thesis, MD simulations are employed to study the molecular basis of elasticity for muscle from the protein titin and for blood clots from the protein fibrinogen. These investigations utilize free dynamics MD to verify experimentally observed conformations of proteins, SMD to probe their response to mechanical forces, and adaptive biasing force (ABF) simulations to measure the free energy landscape of tertiary structure transformations. Several domains of titin are investigated in detail: the Z1Z2 domains bound to the protein telethonin at one end of the long protein chain in a relatively immobile region of the muscle fiber, and the I91 domain and 6-Ig tandem 165-70 located at titin's flexible I-band. SMD simulations of the Z1Z2-telethonin complex reveal that telethonin likely functions as an anchor that tightly tethers titin to one end of the muscle fiber so that titin has a stable base to stretch from. ABF simulations of the Z1Z2 and 165-70 domains suggest strongly that the connected domains function as a large entropic spring when stretched from a loose chain to a tight chain but without unfolding individual domains, an example of so-called tertiary structure elasticity. Finally, SMD simulations of the I91 domain were performed to address the timescale disparity between simulations and experiments, demonstrating that even fast simulations capture faithfully protein rupture events. SMD simulations on the blood clot protein fibrinogen reveal that the source of elasticity observed for blood clots arises from a set of intertwined helices that form the core region of the protein. Upon mechanical tension, fibrinogen's coiled-coils unfold according to helical density, rupturing in the order of double helix, triple helix, and finally quadruple helix. All together, these studies on titin and fibrinogen shed light on the how different protein architectures behave as molecular springs.","Made available in DSpace on 2014-12-17T22:22:49Z (GMT). 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