{"id":{"repo_id":"uwo","oai_identifier":"oai:uwo.scholaris.ca:20.500.14721/32945"},"canonical_url":"https://search.dev.ndltd.org/etd/uwo/oai:uwo.scholaris.ca:20.500.14721/32945","repository":{"repo_id":"uwo","name":"Western University","base_url":"https://uwo.scholaris.ca/server/oai/request"},"display":{"title":"A Highly Charged Topic: Intrinsically Disordered Proteins and Protein pKa Values","abstract":"Intrinsically disordered proteins (IDPs) are known not only for their roles in disease but also for their conformational flexibility, which makes them elusive for experimentation. We consider the role played by theory and simulation in resolving important questions pertaining to IDP structure and dynamics, as well as the nature of the charged residues (e.g., glutamate, lysine, etc.) that enrich them. Specifically, we investigated how the deep learning trained AlphaFold2 (AF2) predictor estimates disorder content, revealing both strong performance in relation to conventional approaches and an important relationship between the AF2 confidence metric and IDP dynamics. We also assessed how modern molecular dynamics (MD) simulations could reproduce the ensembles of two highly charged peptides at various protonation states and two model IDPs for which new experimental data are available. Our results revealed notable performance discrepancies and the impact of a new Amber force field variant on the resultant structures. The charged residues enriched in IDPs are protonatable; depending on their pKa values, they will be (de)protonated at a specific solution pH. We considered how MD simulations alongside non-equilibrium free energy methods and theory could be used to compute coupled and uncoupled pKa values for more than 140 amino acid residues spanning 13 proteins. We achieved performance that matched or exceeded several state-of-the-art alternative approaches.","abstract_html":"Intrinsically disordered proteins (IDPs) are known not only for their roles in disease but also for their conformational flexibility, which makes them elusive for experimentation. We consider the role played by theory and simulation in resolving important questions pertaining to IDP structure and dynamics, as well as the nature of the charged residues (e.g., glutamate, lysine, etc.) that enrich them. Specifically, we investigated how the deep learning trained AlphaFold2 (AF2) predictor estimates disorder content, revealing both strong performance in relation to conventional approaches and an important relationship between the AF2 confidence metric and IDP dynamics. We also assessed how modern molecular dynamics (MD) simulations could reproduce the ensembles of two highly charged peptides at various protonation states and two model IDPs for which new experimental data are available. Our results revealed notable performance discrepancies and the impact of a new Amber force field variant on the resultant structures. The charged residues enriched in IDPs are protonatable; depending on their pKa values, they will be (de)protonated at a specific solution pH. We considered how MD simulations alongside non-equilibrium free energy methods and theory could be used to compute coupled and uncoupled pKa values for more than 140 amino acid residues spanning 13 proteins. We achieved performance that matched or exceeded several state-of-the-art alternative approaches.","abstract_has_math":false,"creators":["Wilson, Carter J."],"institution":"The University of Western Ontario","degree_name":"M Sc","degree_level":null,"degree_discipline":"Applied Mathematics","degree_department":null,"school":null,"contributors":[],"advisors":["Karttunen, Mikko","Choy, Wing-Yiu"],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-04-21","date_published":"2023-04-21","updated_at":"2026-07-27T21:56:14Z","subjects":["molecular dynamics simulation","intrinsically disordered proteins","protein electrostatics","free energy methods","computational biophysics"],"languages":["en_ca"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/20.500.14721/32945","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Karttunen, Mikko","Choy, Wing-Yiu"]},{"key":"dc:creator","label":"Author","values":["Wilson, Carter J."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-07-10T19:39:33Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2025-07-10T19:39:33Z"]},{"key":"dc:date.issued","label":"Date","values":["2023-04-21"]},{"key":"dc:publisher","label":"Institution","values":["The University of Western Ontario"]},{"key":"dc:type","label":"Dc Type","values":["thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Applied Mathematics"]},{"key":"thesis:degree_name","label":"Degree Name","values":["M Sc"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["molecular dynamics simulation","intrinsically disordered proteins","protein electrostatics","free energy methods","computational biophysics"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en_ca"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/20.500.14721/32945"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The thesis cover page in the PDF document includes references to Western University’s previous institutional repository platform, known as Scholarship@Western, and links to that platform (beginning with ir.lib.uwo.ca). In citing or referring to this thesis, use the DOI or handle from this page instead. Sample citation: Author name, \"Thesis title.\" (Year). Western University Open Repository. https://doi.org/10.71858/123456."]},{"key":"dc:description.abstract","label":"Abstract","values":["Intrinsically disordered proteins (IDPs) are known not only for their roles in disease but also for their conformational flexibility, which makes them elusive for experimentation. We consider the role played by theory and simulation in resolving important questions pertaining to IDP structure and dynamics, as well as the nature of the charged residues (e.g., glutamate, lysine, etc.) that enrich them. Specifically, we investigated how the deep learning trained AlphaFold2 (AF2) predictor estimates disorder content, revealing both strong performance in relation to conventional approaches and an important relationship between the AF2 confidence metric and IDP dynamics. We also assessed how modern molecular dynamics (MD) simulations could reproduce the ensembles of two highly charged peptides at various protonation states and two model IDPs for which new experimental data are available. Our results revealed notable performance discrepancies and the impact of a new Amber force field variant on the resultant structures. The charged residues enriched in IDPs are protonatable; depending on their pKa values, they will be (de)protonated at a specific solution pH. We considered how MD simulations alongside non-equilibrium free energy methods and theory could be used to compute coupled and uncoupled pKa values for more than 140 amino acid residues spanning 13 proteins. We achieved performance that matched or exceeded several state-of-the-art alternative approaches."]},{"key":"dc:title","label":"Title","values":["A Highly Charged Topic: Intrinsically Disordered Proteins and Protein pKa Values"]}]}],"canonical_facts":{"dc:contributor.advisor":["Karttunen, Mikko","Choy, Wing-Yiu"],"dc:creator":["Wilson, Carter J."],"dc:date.accessioned":["2025-07-10T19:39:33Z"],"dc:date.available":["2025-07-10T19:39:33Z"],"dc:date.issued":["2023-04-21"],"dc:description":["The thesis cover page in the PDF document includes references to Western University’s previous institutional repository platform, known as Scholarship@Western, and links to that platform (beginning with ir.lib.uwo.ca). In citing or referring to this thesis, use the DOI or handle from this page instead. Sample citation: Author name, \"Thesis title.\" (Year). Western University Open Repository. https://doi.org/10.71858/123456."],"dc:description.abstract":["Intrinsically disordered proteins (IDPs) are known not only for their roles in disease but also for their conformational flexibility, which makes them elusive for experimentation. We consider the role played by theory and simulation in resolving important questions pertaining to IDP structure and dynamics, as well as the nature of the charged residues (e.g., glutamate, lysine, etc.) that enrich them. Specifically, we investigated how the deep learning trained AlphaFold2 (AF2) predictor estimates disorder content, revealing both strong performance in relation to conventional approaches and an important relationship between the AF2 confidence metric and IDP dynamics. We also assessed how modern molecular dynamics (MD) simulations could reproduce the ensembles of two highly charged peptides at various protonation states and two model IDPs for which new experimental data are available. Our results revealed notable performance discrepancies and the impact of a new Amber force field variant on the resultant structures. The charged residues enriched in IDPs are protonatable; depending on their pKa values, they will be (de)protonated at a specific solution pH. We considered how MD simulations alongside non-equilibrium free energy methods and theory could be used to compute coupled and uncoupled pKa values for more than 140 amino acid residues spanning 13 proteins. We achieved performance that matched or exceeded several state-of-the-art alternative approaches."],"dc:identifier.uri":["https://hdl.handle.net/20.500.14721/32945"],"dc:language.iso":["en_ca"],"dc:publisher":["The University of Western Ontario"],"dc:subject":["molecular dynamics simulation","intrinsically disordered proteins","protein electrostatics","free energy methods","computational biophysics"],"dc:title":["A Highly Charged Topic: Intrinsically Disordered Proteins and Protein pKa Values"],"dc:type":["thesis"],"thesis:degree_discipline":["Applied Mathematics"],"thesis:degree_name":["M Sc"]},"updated_at":"2026-07-27T21:56:14Z"}