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dc.contributor.authorWise-Scira O.en_US
dc.contributor.authorAloglu, A.K.en_US
dc.contributor.authorDunn, A.en_US
dc.contributor.authorSakallioglu I.T.en_US
dc.contributor.authorCoskuner O.en_US
dc.date.accessioned2016-02-08T09:39:57Z
dc.date.available2016-02-08T09:39:57Z
dc.date.issued2013en_US
dc.identifier.issn19487193
dc.identifier.urihttp://hdl.handle.net/11693/21031
dc.description.abstractThe genetic missense A30P mutation of the wild-type α-synuclein protein results in the replacement of the 30th amino acid residue from alanine (Ala) to proline (Pro) and was initially found in the members of a German family who developed Parkinson's disease. Even though the structures of these proteins have been measured before, detailed understanding about the structures and their relationships with free energy landscapes is lacking, which is of interest to provide insights into the pathogenic mechanism of Parkinson's disease. We report the secondary and tertiary structures and conformational free energy landscapes of the wild-type and A30P mutant-type α-synuclein proteins in an aqueous solution environment via extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations. In addition, we present the residual secondary structure component transition stabilities at the atomic level with dynamics in terms of free energy change calculations using a new strategy that we reported most recently. Our studies yield new interesting results; for instance, we find that the A30P mutation has local as well as long-range effects on the structural properties of the wild-type α-synuclein protein. The helical content at Ala18-Gly31 is less prominent in comparison to the wild-type α-synuclein protein. The β-sheet structure abundance decreases in the N-terminal region upon A30P mutation of the wild-type α-synuclein, whereas the NAC and C-terminal regions possess larger tendencies for β-sheet structure formation. Long-range intramolecular protein interactions are less abundant upon A30P mutation, especially between the NAC and C-terminal regions, which is linked to the less compact and less stable structures of the A30P mutant-type rather than the wild-type α-synuclein protein. Results including the usage of our new strategy for secondary structure transition stabilities show that the A30P mutant-type α-synuclein tendency toward aggregation is higher than the wild-type α-synuclein but we also find that the C-terminal and NAC regions of the A30P mutant-type α-synuclein are reactive toward fibrillzation and aggregation based on atomic level studies with dynamics in an aqueous solution environment. Therefore, we propose that small molecules or drugs blocking the specific residues, which we report herein, located in the NAC- and C-terminal regions of the A30P mutant-type α-synuclein protein might help to reduce the toxicity of the A30P mutant-type α-synuclein protein. © 2013 American Chemical Society.en_US
dc.language.isoEnglishen_US
dc.source.titleACS Chemical Neuroscienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1021/cn300198qen_US
dc.subjectα-Synucleinen_US
dc.subjectfree energy landscapeen_US
dc.subjectgenetic missense mutationen_US
dc.subjectmolecular dynamics simulationsen_US
dc.subjectalpha synucleinen_US
dc.subjecta30 mutant typeen_US
dc.subjectaqueous solutionen_US
dc.subjectarticleen_US
dc.subjectbeta sheeten_US
dc.subjectenergy transferen_US
dc.subjectgene mutationen_US
dc.subjectmolecular dynamicsen_US
dc.subjectmolecular libraryen_US
dc.subjectpriority journalen_US
dc.subjectprotein aggregationen_US
dc.subjectprotein interactionen_US
dc.subjectprotein structureen_US
dc.subjectthermodynamicsen_US
dc.subjectwild typeen_US
dc.subjectAlanineen_US
dc.subjectalpha-Synucleinen_US
dc.subjectEnergy Metabolismen_US
dc.subjectHumansen_US
dc.subjectMolecular Dynamics Simulationen_US
dc.subjectMutant Proteinsen_US
dc.subjectMutation, Missenseen_US
dc.subjectProlineen_US
dc.subjectProtein Structure, Secondaryen_US
dc.subjectProtein Structure, Tertiaryen_US
dc.titleStructures and free energy landscapes of the wild-type and A30P mutant-type α-synuclein proteins with dynamicsen_US
dc.typeArticleen_US
dc.departmentDepartment of Chemistryen_US
dc.citation.spage486en_US
dc.citation.epage497en_US
dc.citation.volumeNumber4en_US
dc.citation.issueNumber3en_US
dc.identifier.doi10.1021/cn300198qen_US


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