{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/89115"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/89115","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Computational investigations of protein dynamics and its implication in cellular functions: two cases on membrane sculpting by protein complexes and molecular origin of Parkinson's disease","abstract":"Proteins are complex machineries dedicated to drive many functions in eukaryotic cells. In this article, two cases of protein dynamics and their implications to cellular functions are discussed with computational approaches: membrane sculpting by F-BAR domains and transient β-hairpin structure in α-synuclein. Interplay between cellular membranes and their peripheral proteins drives many processes in eukaryotic cells. Proteins of the Bin/Amphiphysin/Rvs (BAR) domain family, in particular, play a role in cellular morphogenesis, for example curving planar membranes into tubular membranes. However, it is still unclear how F-BAR domain proteins act on membranes. Electron microscopy revealed that, in vitro, F-BAR proteins form regular lattices on cylindrically deformed membrane surfaces. Using all-atom and coarse-grained (CG) molecular dynamics simulations, we show that such lattices, indeed, induce tubes of observed radii. A 250 ns all-atom simulation reveals that F-BAR domain curves membranes via the so-called “scaffolding” mechanism. Plasticity of the F-BAR domain permits conformational change in response to membrane interaction, via partial unwinding of the domain’s 3-helix bundle structure. A CG simulation covering more than 350 µs provides a dynamic picture of membrane tubulation by lattices of F-BAR domains. A series of CG simulations identified the optimal lattice type for membrane sculpting, which matches closely the lattices seen through cryo-electron microscopy. The molecular dynamics study others, thereby, both a large-scale picture of membrane sculpting by F-BAR domain lattices as well as atomic-level dynamic information about the involvement of the individual F-BAR domain and its interactions with partner F-BAR domains and membrane in the sculpting process. Parkinson’s disease is a common neurodegenerative disorder that originates from the intrinsically disordered peptide α-synuclein aggregating into fibrils. It remains unclear how α-synuclein monomers undergo conformational changes leading to aggregation and formation of fibrils characteristic for the disease. In the present study, we perform molecular dynamics simulations (over 150 μs in aggregated time) using a hybrid-resolution model, PACE, to characterize in atomic detail structural ensembles of wild type and mutant monomeric α-synuclein in aqueous solution. The simulations reproduce structural properties of α-synuclein characterized in experiments, such as secondary structure content, long-range contacts, chemical shifts and 3J(HNHCα )-coupling constants. Most notably, the simulations reveal that a short fragment encompassing region 38-53, adjacent to the non-Amyloid-β component region, exhibits a high probability of forming a β-hairpin; this fragment, when isolated from the remainder of α-synuclein, fluctuates frequently into its β-hairpin conformation. Two disease-prone mutations, namely A30P and A53T, significantly accelerate the formation of a β-hairpin in the stated fragment. We conclude that the formation of a β-hairpin in region 38-53 is a key event during α-synuclein aggregation. We predict further that the G47V mutation impedes the formation of a turn in the β-hairpin and slows down β-hairpin formation, thereby retarding α-synuclein aggregation.","abstract_html":"Proteins are complex machineries dedicated to drive many functions in eukaryotic cells. In this article, two cases of protein dynamics and their implications to cellular functions are discussed with computational approaches: membrane sculpting by F-BAR domains and transient β-hairpin structure in α-synuclein. Interplay between cellular membranes and their peripheral proteins drives many processes in eukaryotic cells. Proteins of the Bin/Amphiphysin/Rvs (BAR) domain family, in particular, play a role in cellular morphogenesis, for example curving planar membranes into tubular membranes. However, it is still unclear how F-BAR domain proteins act on membranes. Electron microscopy revealed that, in vitro, F-BAR proteins form regular lattices on cylindrically deformed membrane surfaces. Using all-atom and coarse-grained (CG) molecular dynamics simulations, we show that such lattices, indeed, induce tubes of observed radii. A 250 ns all-atom simulation reveals that F-BAR domain curves membranes via the so-called “scaffolding” mechanism. Plasticity of the F-BAR domain permits conformational change in response to membrane interaction, via partial unwinding of the domain’s 3-helix bundle structure. A CG simulation covering more than 350 µs provides a dynamic picture of membrane tubulation by lattices of F-BAR domains. A series of CG simulations identified the optimal lattice type for membrane sculpting, which matches closely the lattices seen through cryo-electron microscopy. The molecular dynamics study others, thereby, both a large-scale picture of membrane sculpting by F-BAR domain lattices as well as atomic-level dynamic information about the involvement of the individual F-BAR domain and its interactions with partner F-BAR domains and membrane in the sculpting process. Parkinson’s disease is a common neurodegenerative disorder that originates from the intrinsically disordered peptide α-synuclein aggregating into fibrils. It remains unclear how α-synuclein monomers undergo conformational changes leading to aggregation and formation of fibrils characteristic for the disease. In the present study, we perform molecular dynamics simulations (over 150 μs in aggregated time) using a hybrid-resolution model, PACE, to characterize in atomic detail structural ensembles of wild type and mutant monomeric α-synuclein in aqueous solution. The simulations reproduce structural properties of α-synuclein characterized in experiments, such as secondary structure content, long-range contacts, chemical shifts and 3J(HNHCα )-coupling constants. Most notably, the simulations reveal that a short fragment encompassing region 38-53, adjacent to the non-Amyloid-β component region, exhibits a high probability of forming a β-hairpin; this fragment, when isolated from the remainder of α-synuclein, fluctuates frequently into its β-hairpin conformation. Two disease-prone mutations, namely A30P and A53T, significantly accelerate the formation of a β-hairpin in the stated fragment. We conclude that the formation of a β-hairpin in region 38-53 is a key event during α-synuclein aggregation. We predict further that the G47V mutation impedes the formation of a turn in the β-hairpin and slows down β-hairpin formation, thereby retarding α-synuclein aggregation.","abstract_has_math":false,"creators":["Yu, Hang"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Biophysics & Computional Biology","degree_department":null,"school":null,"contributors":["Schulten, Klaus","Tajkhorshid, Emad","Grosman, Claudio","Luthey-Schulten, Zan"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2016,"date_issued":"2016-03-02T20:23:32Z","date_published":"2016-03-02T20:23:32Z","updated_at":"2026-07-22T22:26:32Z","subjects":["Molecular dynamics simulation","molecular dynamics (MD) simulation","Protein","Membrane","Curvature","F-BAR domain","Parkinson’s disease","α-synuclein","β-hairpin"],"languages":["en"],"rights":["Copyright 2015 Hang Yu"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/89115","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Schulten, Klaus","Tajkhorshid, Emad","Grosman, Claudio","Luthey-Schulten, Zan"]},{"key":"dc:creator","label":"Author","values":["Yu, Hang"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2016-03-02T20:23:32Z","2015-11-20","2015-12"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biophysics & Computional 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":["Molecular dynamics simulation","molecular dynamics (MD) simulation","Protein","Membrane","Curvature","F-BAR domain","Parkinson’s disease","α-synuclein","β-hairpin"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2015 Hang Yu"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/89115"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Proteins are complex machineries dedicated to drive many functions in eukaryotic cells. In this article, two cases of protein dynamics and their implications to cellular functions are discussed with computational approaches: membrane sculpting by F-BAR domains and transient β-hairpin structure in α-synuclein. Interplay between cellular membranes and their peripheral proteins drives many processes in eukaryotic cells. Proteins of the Bin/Amphiphysin/Rvs (BAR) domain family, in particular, play a role in cellular morphogenesis, for example curving planar membranes into tubular membranes. However, it is still unclear how F-BAR domain proteins act on membranes. Electron microscopy revealed that, in vitro, F-BAR proteins form regular lattices on cylindrically deformed membrane surfaces. Using all-atom and coarse-grained (CG) molecular dynamics simulations, we show that such lattices, indeed, induce tubes of observed radii. A 250 ns all-atom simulation reveals that F-BAR domain curves membranes via the so-called “scaffolding” mechanism. Plasticity of the F-BAR domain permits conformational change in response to membrane interaction, via partial unwinding of the domain’s 3-helix bundle structure. A CG simulation covering more than 350 µs provides a dynamic picture of membrane tubulation by lattices of F-BAR domains. A series of CG simulations identified the optimal lattice type for membrane sculpting, which matches closely the lattices seen through cryo-electron microscopy. The molecular dynamics study others, thereby, both a large-scale picture of membrane sculpting by F-BAR domain lattices as well as atomic-level dynamic information about the involvement of the individual F-BAR domain and its interactions with partner F-BAR domains and membrane in the sculpting process. Parkinson’s disease is a common neurodegenerative disorder that originates from the intrinsically disordered peptide α-synuclein aggregating into fibrils. It remains unclear how α-synuclein monomers undergo conformational changes leading to aggregation and formation of fibrils characteristic for the disease. In the present study, we perform molecular dynamics simulations (over 150 μs in aggregated time) using a hybrid-resolution model, PACE, to characterize in atomic detail structural ensembles of wild type and mutant monomeric α-synuclein in aqueous solution. The simulations reproduce structural properties of α-synuclein characterized in experiments, such as secondary structure content, long-range contacts, chemical shifts and 3J(HNHCα )-coupling constants. Most notably, the simulations reveal that a short fragment encompassing region 38-53, adjacent to the non-Amyloid-β component region, exhibits a high probability of forming a β-hairpin; this fragment, when isolated from the remainder of α-synuclein, fluctuates frequently into its β-hairpin conformation. Two disease-prone mutations, namely A30P and A53T, significantly accelerate the formation of a β-hairpin in the stated fragment. We conclude that the formation of a β-hairpin in region 38-53 is a key event during α-synuclein aggregation. We predict further that the G47V mutation impedes the formation of a turn in the β-hairpin and slows down β-hairpin formation, thereby retarding α-synuclein aggregation.","Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2017-12-01","The student, Hang Yu, accepted the attached license on 2015-11-18 at 09:47.","The student, Hang Yu, submitted this Dissertation for approval on 2015-11-18 at 10:05.","This Dissertation was approved for publication on 2015-11-20 at 08:49.","DSpace SAF Submission Ingestion Package generated from Vireo submission #8800 on 2016-03-02 at 14:05:51","Made available in DSpace on 2016-03-02T20:23:32Z (GMT). No. of bitstreams: 2 YU-DISSERTATION-2015.pdf: 65003759 bytes, checksum: 532de3c804a1a0ed58319ec57a9b54ea (MD5) LICENSE.txt: 4204 bytes, checksum: e3e65555120cb03edc9f752e95ca88db (MD5) Previous issue date: 2015-11-20","Embargo set by: Seth Robbins for item 91317 Lift date: 2018-03-02T20:24:31Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","Open"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Computational investigations of protein dynamics and its implication in cellular functions: two cases on membrane sculpting by protein complexes and molecular origin of Parkinson's disease"]}]}],"canonical_facts":{"dc:contributor":["Schulten, Klaus","Tajkhorshid, Emad","Grosman, Claudio","Luthey-Schulten, Zan"],"dc:creator":["Yu, Hang"],"dc:date":["2016-03-02T20:23:32Z","2015-11-20","2015-12"],"dc:description":["Proteins are complex machineries dedicated to drive many functions in eukaryotic cells. In this article, two cases of protein dynamics and their implications to cellular functions are discussed with computational approaches: membrane sculpting by F-BAR domains and transient β-hairpin structure in α-synuclein. Interplay between cellular membranes and their peripheral proteins drives many processes in eukaryotic cells. Proteins of the Bin/Amphiphysin/Rvs (BAR) domain family, in particular, play a role in cellular morphogenesis, for example curving planar membranes into tubular membranes. However, it is still unclear how F-BAR domain proteins act on membranes. Electron microscopy revealed that, in vitro, F-BAR proteins form regular lattices on cylindrically deformed membrane surfaces. Using all-atom and coarse-grained (CG) molecular dynamics simulations, we show that such lattices, indeed, induce tubes of observed radii. A 250 ns all-atom simulation reveals that F-BAR domain curves membranes via the so-called “scaffolding” mechanism. Plasticity of the F-BAR domain permits conformational change in response to membrane interaction, via partial unwinding of the domain’s 3-helix bundle structure. A CG simulation covering more than 350 µs provides a dynamic picture of membrane tubulation by lattices of F-BAR domains. A series of CG simulations identified the optimal lattice type for membrane sculpting, which matches closely the lattices seen through cryo-electron microscopy. The molecular dynamics study others, thereby, both a large-scale picture of membrane sculpting by F-BAR domain lattices as well as atomic-level dynamic information about the involvement of the individual F-BAR domain and its interactions with partner F-BAR domains and membrane in the sculpting process. Parkinson’s disease is a common neurodegenerative disorder that originates from the intrinsically disordered peptide α-synuclein aggregating into fibrils. It remains unclear how α-synuclein monomers undergo conformational changes leading to aggregation and formation of fibrils characteristic for the disease. In the present study, we perform molecular dynamics simulations (over 150 μs in aggregated time) using a hybrid-resolution model, PACE, to characterize in atomic detail structural ensembles of wild type and mutant monomeric α-synuclein in aqueous solution. The simulations reproduce structural properties of α-synuclein characterized in experiments, such as secondary structure content, long-range contacts, chemical shifts and 3J(HNHCα )-coupling constants. Most notably, the simulations reveal that a short fragment encompassing region 38-53, adjacent to the non-Amyloid-β component region, exhibits a high probability of forming a β-hairpin; this fragment, when isolated from the remainder of α-synuclein, fluctuates frequently into its β-hairpin conformation. Two disease-prone mutations, namely A30P and A53T, significantly accelerate the formation of a β-hairpin in the stated fragment. We conclude that the formation of a β-hairpin in region 38-53 is a key event during α-synuclein aggregation. We predict further that the G47V mutation impedes the formation of a turn in the β-hairpin and slows down β-hairpin formation, thereby retarding α-synuclein aggregation.","Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2017-12-01","The student, Hang Yu, accepted the attached license on 2015-11-18 at 09:47.","The student, Hang Yu, submitted this Dissertation for approval on 2015-11-18 at 10:05.","This Dissertation was approved for publication on 2015-11-20 at 08:49.","DSpace SAF Submission Ingestion Package generated from Vireo submission #8800 on 2016-03-02 at 14:05:51","Made available in DSpace on 2016-03-02T20:23:32Z (GMT). No. of bitstreams: 2 YU-DISSERTATION-2015.pdf: 65003759 bytes, checksum: 532de3c804a1a0ed58319ec57a9b54ea (MD5) LICENSE.txt: 4204 bytes, checksum: e3e65555120cb03edc9f752e95ca88db (MD5) Previous issue date: 2015-11-20","Embargo set by: Seth Robbins for item 91317 Lift date: 2018-03-02T20:24:31Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system","Open"],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/2142/89115"],"dc:language":["en"],"dc:rights":["Copyright 2015 Hang Yu"],"dc:subject":["Molecular dynamics simulation","molecular dynamics (MD) simulation","Protein","Membrane","Curvature","F-BAR domain","Parkinson’s disease","α-synuclein","β-hairpin"],"dc:title":["Computational investigations of protein dynamics and its implication in cellular functions: two cases on membrane sculpting by protein complexes and molecular origin of Parkinson's disease"],"dc:type":["text"],"thesis:degree_discipline":["Biophysics & Computional Biology"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:26:32Z"}