Uncovering the molecular mechanisms of cardiac ion channels’ regulation by lipids and pore formation in membranes using computer simulations
| dc.contributor.advisor | Tieleman, Peter DP | |
| dc.contributor.author | Mesa Galloso, Haydee | |
| dc.contributor.committeemember | MacCallum, Justin Laine | |
| dc.contributor.committeemember | Zaremberg, Vanina | |
| dc.contributor.committeemember | Prenner, Elmar Josef | |
| dc.contributor.committeemember | Van Petegem, Filip | |
| dc.date | 2023-11 | |
| dc.date.accessioned | 2023-09-07T20:15:13Z | |
| dc.date.available | 2023-09-07T20:15:13Z | |
| dc.date.issued | 2023-08-30 | |
| dc.description.abstract | Membranes are complex cellular structures consisting of many different lipid types, a variety of bound proteins, and other molecules. Growing evidence suggests that membranes and lipids play significant bioactive roles in modulating protein function across several cellular processes. Molecular dynamic (MD) simulations have proven to be a valuable method to study lipid organization and membrane protein activity. In this thesis, I used MD simulations to study how lipids regulate two types of membrane proteins: ion channels and pore-forming proteins. Previous simulations and experimental studies showed that polyunsaturated fatty acids (PUFAs) activate KCNQ1 channels while blocking hERG channels. However, some questions regarding how the channel state or PUFA structural properties influence their molecular mechanisms remained unclear. In part of my work, I built a cardiomyocyte membrane model to study the molecular mechanism underlying the interactions between PUFAs and two voltage-gated potassium channels involved in the cardiac action potential: KCNQ1 and hERG. My results revealed that when KCNQ1 voltage sensor domain (VSD) was in the resting state or ‘down’ conformation, the PUFAs established short-lasting interactions that were different from the long-lasting interactions previously observed in the KCNQ1 intermediate state, where the VSD is in the ‘up’ conformation. Additionally, my studies showed that the number of double bonds in the PUFA acyl tail and the size of the polar head regulates their affinity for KCNQ1. Moreover, MD simulations of the hERG channel in the cardiomyocyte membrane unveiled the PUFA interacting site on hERG at the interface between the VSD and the PD in the open and closed states. I anticipate that this detailed molecular understanding of how PUFAs interact with KCNQ1 and hERG will aid in developing future drugs that utilize these mechanisms. As part of this work, I also studied the pore-forming mechanism of the N-terminal peptide StII1-30, derived from the actinoporin StII. My results revealed that this peptide followed a toroidal pore formation mechanism. Additionally, I unveiled the role of curved lipids as cofactors in the formation of toroidal pores. This work has the potential to lead to strategies for the rational use of these peptides as immunotoxins for immunotherapy in cancer tumors. The overall work in this thesis enhances our understanding of lipid-protein interactions in voltage-gated ion channels and the mechanism underlying pore formation by lytic peptides. | |
| dc.identifier.citation | Mesa Galloso, H. (2023). Uncovering the molecular mechanisms of cardiac ion channels’ regulation by lipids and pore formation in membranes using computer simulations (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. | |
| dc.identifier.uri | https://hdl.handle.net/1880/116979 | |
| dc.identifier.uri | https://dx.doi.org/10.11575/PRISM/41823 | |
| dc.language.iso | en | |
| dc.publisher.faculty | Graduate Studies | |
| dc.publisher.institution | University of Calgary | |
| dc.rights | University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. | |
| dc.subject | moleculer dynamic simulations | |
| dc.subject | pore forming proteins | |
| dc.subject | lipid-protein interactions | |
| dc.subject | voltage-gated potassium channels | |
| dc.subject.classification | Biophysics | |
| dc.title | Uncovering the molecular mechanisms of cardiac ion channels’ regulation by lipids and pore formation in membranes using computer simulations | |
| dc.type | doctoral thesis | |
| thesis.degree.discipline | Biological Sciences | |
| thesis.degree.grantor | University of Calgary | |
| thesis.degree.name | Doctor of Philosophy (PhD) | |
| ucalgary.thesis.accesssetbystudent | I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible. |