{"id":{"repo_id":"uic","oai_identifier":"oai:figshare.com:article/31451335"},"canonical_url":"https://search.dev.ndltd.org/etd/uic/oai:figshare.com:article/31451335","repository":{"repo_id":"uic","name":"University of Illinois - Chicago","base_url":"https://api.figshare.com/v2/oai"},"display":{"title":"Decoding the Sequence-Dependent Properties of Intrinsically Disordered Proteins","abstract":"A core principle of structural biology is the sequence-structure-function paradigm, whereby a proteins sequence codes for a specific structure that complements its binding partner, thus imparting functionality. Intrinsically disordered proteins (IDPs) lack a well-defined structure yet manage to interact with a variety of partners. At a basic level we can use amino-acid sequences to predict disordered content, but the sequence profile of an IDP can tell us so much more. By leveraging all-atom MD simulations, this dissertation aims to dissect the sequence-dependent properties of IDPs to develop governing rules that can be applied to the wider disordered proteome. We first look at sequence-dependent dynamics. Using long timescale MD simulations on a set of diverse IDPs, we show that fast motions can be attributed to glycine residues, while transient secondary structure and local or long-range intramolecular interactions facilitate slow dynamics. We noted that slowed regions had significant overlap with drug-interacting residues in IDPs. With that in mind, we reparametrized our IDP-dynamic prediction method (SeqDYN) with chemical shift perturbation data to develop DIRseq, a prediction method for identifying IDP drug binding regions. IDPs are known to readily undergo homogenous liquid-liquid phase separation (LLPS) under certain conditions, however variations in salt concentration have been shown to have disparate effects and can even enhance phase separation beyond 1 M NaCl. Through the lens of A1-LCD we simulate an 8-chain model in low- to high-NaCl concentrations and identify direct and indirect roles salt plays in IDP-LLPS. We use this to then classify a group of 26 IDPs into four modes of sequence-dependent salt-LLPS effects. Membranes also serve as key IDP binding partners, as they can impart both function and dysfunction. We first investigated tau K19, which forms amphipathic helices in acidic membranes. The nature of the tau-membrane interaction mimics that of the tau-microtubule interaction as seen in cryo-EM studies, and we propose a method in which membrane mediates tau transfer to microtubules. Next, we use enhanced sampling techniques to determine a membrane-assisted fibril forming pathway for the IDP α-synuclein, which gives us insight to Parkinson’s disease specific fibril formation.","abstract_html":"A core principle of structural biology is the sequence-structure-function paradigm, whereby a proteins sequence codes for a specific structure that complements its binding partner, thus imparting functionality. Intrinsically disordered proteins (IDPs) lack a well-defined structure yet manage to interact with a variety of partners. At a basic level we can use amino-acid sequences to predict disordered content, but the sequence profile of an IDP can tell us so much more. By leveraging all-atom MD simulations, this dissertation aims to dissect the sequence-dependent properties of IDPs to develop governing rules that can be applied to the wider disordered proteome. We first look at sequence-dependent dynamics. Using long timescale MD simulations on a set of diverse IDPs, we show that fast motions can be attributed to glycine residues, while transient secondary structure and local or long-range intramolecular interactions facilitate slow dynamics. We noted that slowed regions had significant overlap with drug-interacting residues in IDPs. With that in mind, we reparametrized our IDP-dynamic prediction method (SeqDYN) with chemical shift perturbation data to develop DIRseq, a prediction method for identifying IDP drug binding regions. IDPs are known to readily undergo homogenous liquid-liquid phase separation (LLPS) under certain conditions, however variations in salt concentration have been shown to have disparate effects and can even enhance phase separation beyond 1 M NaCl. Through the lens of A1-LCD we simulate an 8-chain model in low- to high-NaCl concentrations and identify direct and indirect roles salt plays in IDP-LLPS. We use this to then classify a group of 26 IDPs into four modes of sequence-dependent salt-LLPS effects. Membranes also serve as key IDP binding partners, as they can impart both function and dysfunction. We first investigated tau K19, which forms amphipathic helices in acidic membranes. The nature of the tau-membrane interaction mimics that of the tau-microtubule interaction as seen in cryo-EM studies, and we propose a method in which membrane mediates tau transfer to microtubules. Next, we use enhanced sampling techniques to determine a membrane-assisted fibril forming pathway for the IDP α-synuclein, which gives us insight to Parkinson’s disease specific fibril formation.","abstract_has_math":false,"creators":["Matthew F MacAinsh (23291569)"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-12-01T00:00:00Z","date_published":"2025-12-01T00:00:00Z","updated_at":"2026-07-27T21:34:24Z","subjects":["Chemistry, Biochemistry","Biophysics, General"],"languages":[],"rights":["In Copyright"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.25417/uic.31451335.v1","outbound_label":"DOI","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Matthew F MacAinsh (23291569)"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2025-12-01T00:00:00Z"]},{"key":"dc:relation","label":"Dc Relation","values":["https://figshare.com/articles/thesis/Decoding_the_Sequence-Dependent_Properties_of_Intrinsically_Disordered_Proteins/31451335"]},{"key":"dc:type","label":"Dc Type","values":["Text","Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Chemistry, Biochemistry","Biophysics, General"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["In Copyright"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["10.25417/uic.31451335.v1"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["A core principle of structural biology is the sequence-structure-function paradigm, whereby a proteins sequence codes for a specific structure that complements its binding partner, thus imparting functionality. Intrinsically disordered proteins (IDPs) lack a well-defined structure yet manage to interact with a variety of partners. At a basic level we can use amino-acid sequences to predict disordered content, but the sequence profile of an IDP can tell us so much more. By leveraging all-atom MD simulations, this dissertation aims to dissect the sequence-dependent properties of IDPs to develop governing rules that can be applied to the wider disordered proteome. We first look at sequence-dependent dynamics. Using long timescale MD simulations on a set of diverse IDPs, we show that fast motions can be attributed to glycine residues, while transient secondary structure and local or long-range intramolecular interactions facilitate slow dynamics. We noted that slowed regions had significant overlap with drug-interacting residues in IDPs. With that in mind, we reparametrized our IDP-dynamic prediction method (SeqDYN) with chemical shift perturbation data to develop DIRseq, a prediction method for identifying IDP drug binding regions. IDPs are known to readily undergo homogenous liquid-liquid phase separation (LLPS) under certain conditions, however variations in salt concentration have been shown to have disparate effects and can even enhance phase separation beyond 1 M NaCl. Through the lens of A1-LCD we simulate an 8-chain model in low- to high-NaCl concentrations and identify direct and indirect roles salt plays in IDP-LLPS. We use this to then classify a group of 26 IDPs into four modes of sequence-dependent salt-LLPS effects. Membranes also serve as key IDP binding partners, as they can impart both function and dysfunction. We first investigated tau K19, which forms amphipathic helices in acidic membranes. The nature of the tau-membrane interaction mimics that of the tau-microtubule interaction as seen in cryo-EM studies, and we propose a method in which membrane mediates tau transfer to microtubules. Next, we use enhanced sampling techniques to determine a membrane-assisted fibril forming pathway for the IDP α-synuclein, which gives us insight to Parkinson’s disease specific fibril formation."]},{"key":"dc:title","label":"Title","values":["Decoding the Sequence-Dependent Properties of Intrinsically Disordered Proteins"]}]}],"canonical_facts":{"dc:creator":["Matthew F MacAinsh (23291569)"],"dc:date":["2025-12-01T00:00:00Z"],"dc:description":["A core principle of structural biology is the sequence-structure-function paradigm, whereby a proteins sequence codes for a specific structure that complements its binding partner, thus imparting functionality. Intrinsically disordered proteins (IDPs) lack a well-defined structure yet manage to interact with a variety of partners. At a basic level we can use amino-acid sequences to predict disordered content, but the sequence profile of an IDP can tell us so much more. By leveraging all-atom MD simulations, this dissertation aims to dissect the sequence-dependent properties of IDPs to develop governing rules that can be applied to the wider disordered proteome. We first look at sequence-dependent dynamics. Using long timescale MD simulations on a set of diverse IDPs, we show that fast motions can be attributed to glycine residues, while transient secondary structure and local or long-range intramolecular interactions facilitate slow dynamics. We noted that slowed regions had significant overlap with drug-interacting residues in IDPs. With that in mind, we reparametrized our IDP-dynamic prediction method (SeqDYN) with chemical shift perturbation data to develop DIRseq, a prediction method for identifying IDP drug binding regions. IDPs are known to readily undergo homogenous liquid-liquid phase separation (LLPS) under certain conditions, however variations in salt concentration have been shown to have disparate effects and can even enhance phase separation beyond 1 M NaCl. Through the lens of A1-LCD we simulate an 8-chain model in low- to high-NaCl concentrations and identify direct and indirect roles salt plays in IDP-LLPS. We use this to then classify a group of 26 IDPs into four modes of sequence-dependent salt-LLPS effects. Membranes also serve as key IDP binding partners, as they can impart both function and dysfunction. We first investigated tau K19, which forms amphipathic helices in acidic membranes. The nature of the tau-membrane interaction mimics that of the tau-microtubule interaction as seen in cryo-EM studies, and we propose a method in which membrane mediates tau transfer to microtubules. Next, we use enhanced sampling techniques to determine a membrane-assisted fibril forming pathway for the IDP α-synuclein, which gives us insight to Parkinson’s disease specific fibril formation."],"dc:identifier":["10.25417/uic.31451335.v1"],"dc:relation":["https://figshare.com/articles/thesis/Decoding_the_Sequence-Dependent_Properties_of_Intrinsically_Disordered_Proteins/31451335"],"dc:rights":["In Copyright"],"dc:subject":["Chemistry, Biochemistry","Biophysics, General"],"dc:title":["Decoding the Sequence-Dependent Properties of Intrinsically Disordered Proteins"],"dc:type":["Text","Thesis"]},"updated_at":"2026-07-27T21:34:24Z"}