{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/79938"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/79938","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"Decrypting the Heat Activation Mechanism of TRPV1 Channel by Molecular Dynamics Simulation","abstract":"Ph.D.","abstract_html":"Ph.D.","abstract_has_math":false,"creators":["Wen, Han"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Zheng, Wenjun","Physics"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-07-30T15:11:16Z","date_published":"2019-07-30T15:11:16Z","updated_at":"2026-07-27T19:05:21Z","subjects":["biophysics","physics"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/79938","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Zheng, Wenjun","Physics"]},{"key":"dc:creator","label":"Author","values":["Wen, Han"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2019-07-30T15:11:16Z","2019","2019-05-14 10:29:29"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Text","Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["biophysics","physics"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/79938"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Ph.D.","The transient receptor potential (TRP) channels are a superfamily of ion channels activated by a diversity of physical and chemical stimuli (such as noxious heat) and involved in many physiological and pathophysiological processes (such as heat and pain sensing). However, the heat activation mechanism of TRP channels remains obscure at the molecular level, which has hindered development of therapeutic antagonists that target these channels with high specificity and low toxicity (e.g., without disrupting the heat-sensing function). Recent solutions of high-resolution structures of TRPV1 (a founding member of the TRP vanilloid subfamily) have paved the way for obtaining detailed structural, dynamic and energetic information critical to the TRP-channel functions by exploiting state-of-the-art computational methods. The molecular dynamics (MD) simulation is the method of choice for exploring the structural dynamics of ion channels at atomic resolution. Towards decrypting the heat activation of TRPV1, we performed extensive simulations in both open and closed states under different temperatures. Starting from the high-resolution closed and open structures of TRPV1 solved by cryo-electron microscopy back in 2013. In the closed-state simulations at 30°C , we observed a stably closed channel constricted at the lower gate (near residue I679), while the upper gate (near residues G643 and M644) is dynamic and undergoes quick opening/closing transitions. In the open-state simulations at 60°C , we found higher conformational variation consistent with a large entropy increase required for the heat activation, and both the lower and upper gates are dynamic with transient opening/closing. Through ensemble-based structural analyses of the closed state versus the open state, we revealed pronounced closed-to-open conformational changes involving the membrane proximal domain (MPD) linker, the outer pore, and the TRP helix, which are accompanied by breaking/forming of a network of closed/open-state specific hydrogen bonds. By comparing the closed-state simulations at 30°C and 60°C , we observed heat-activated conformational changes in the MPD linker, the outer pore, and the TRP helix that resemble the closed-to-open conformational changes, along with partial formation of the open-state specific hydrogen bonds. Some of the residues involved in the above key hydrogen bonds were validated by previous mutational studies."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Decrypting the Heat Activation Mechanism of TRPV1 Channel by Molecular Dynamics Simulation"]}]}],"canonical_facts":{"dc:contributor":["Zheng, Wenjun","Physics"],"dc:creator":["Wen, Han"],"dc:date":["2019-07-30T15:11:16Z","2019","2019-05-14 10:29:29"],"dc:description":["Ph.D.","The transient receptor potential (TRP) channels are a superfamily of ion channels activated by a diversity of physical and chemical stimuli (such as noxious heat) and involved in many physiological and pathophysiological processes (such as heat and pain sensing). However, the heat activation mechanism of TRP channels remains obscure at the molecular level, which has hindered development of therapeutic antagonists that target these channels with high specificity and low toxicity (e.g., without disrupting the heat-sensing function). Recent solutions of high-resolution structures of TRPV1 (a founding member of the TRP vanilloid subfamily) have paved the way for obtaining detailed structural, dynamic and energetic information critical to the TRP-channel functions by exploiting state-of-the-art computational methods. The molecular dynamics (MD) simulation is the method of choice for exploring the structural dynamics of ion channels at atomic resolution. Towards decrypting the heat activation of TRPV1, we performed extensive simulations in both open and closed states under different temperatures. Starting from the high-resolution closed and open structures of TRPV1 solved by cryo-electron microscopy back in 2013. In the closed-state simulations at 30°C , we observed a stably closed channel constricted at the lower gate (near residue I679), while the upper gate (near residues G643 and M644) is dynamic and undergoes quick opening/closing transitions. In the open-state simulations at 60°C , we found higher conformational variation consistent with a large entropy increase required for the heat activation, and both the lower and upper gates are dynamic with transient opening/closing. Through ensemble-based structural analyses of the closed state versus the open state, we revealed pronounced closed-to-open conformational changes involving the membrane proximal domain (MPD) linker, the outer pore, and the TRP helix, which are accompanied by breaking/forming of a network of closed/open-state specific hydrogen bonds. By comparing the closed-state simulations at 30°C and 60°C , we observed heat-activated conformational changes in the MPD linker, the outer pore, and the TRP helix that resemble the closed-to-open conformational changes, along with partial formation of the open-state specific hydrogen bonds. Some of the residues involved in the above key hydrogen bonds were validated by previous mutational studies."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/79938"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["biophysics","physics"],"dc:title":["Decrypting the Heat Activation Mechanism of TRPV1 Channel by Molecular Dynamics Simulation"],"dc:type":["Text","Dissertation"]},"updated_at":"2026-07-27T19:05:21Z"}