Structures and Free Energy Landscapes of the Wild-Type and A30P Mutant-Type α-Synuclein Proteins with Dynamics

Wise-Scira, Olivia; Aloglu, Ahmet Kemal; Dunn, Aquila; Sakallioglu, Isin T.; Coskuner, Orkid

doi:10.1021/cn300198q

Cited by 34 publications

(50 citation statements)

References 63 publications

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“…The stability of secondary structure transitions between two specific secondary structure components per residue for the wild-type (WT) and A53T mutant-type (A53T) αS proteins based on free energy calculations performed using our recently developed theoretical strategy. 44,46 The color scale corresponds to the free energy value associated with the specific secondary structure transition between two secondary structure components for a specific residue. that the intramolecular interactions of the C-terminal region with the N-terminal or NAC regions almost disappear upon A53T mutation.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Structures and Free Energy Landscapes of the A53T Mutant-Type α-Synuclein Protein and Impact of A53T Mutation on the Structures of the Wild-Type α-Synuclein Protein with Dynamics

Coskuner

Wise-Scira

2013

ACS Chem. Neurosci.

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The A53T genetic missense mutation of the wild-type α-synuclein (αS) protein was initially identified in Greek and Italian families with familial Parkinson's disease. Detailed understanding of the structures and the changes induced in the wild-type αS structure by the A53T mutation, as well as establishing the direct relationships between the rapid conformational changes and free energy landscapes of these intrinsically disordered fibrillogenic proteins, helps to enhance our fundamental knowledge and to gain insights into the pathogenic mechanism of Parkinson's disease. We employed extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations to determine the secondary and tertiary structural properties as well as the conformational free energy surfaces of the wild-type and A53T mutant-type αS proteins in an aqueous solution medium using both implicit and explicit water models. The confined aqueous volume effect in the simulations of disordered proteins using an explicit model for water is addressed for a model disordered protein. We also assessed the stabilities of the residual secondary structure component interconversions in αS based on free energy calculations at the atomic level with dynamics using our recently developed theoretical strategy. To the best of our knowledge, this study presents the first detailed comparison of the structural properties linked directly to the conformational free energy landscapes of the monomeric wild-type and A53T mutant-type α-synuclein proteins in an aqueous solution environment. Results demonstrate that the β-sheet structure is significantly more altered than the helical structure upon A53T mutation of the monomeric wild-type αS protein in aqueous solution. The β-sheet content close to the mutation site in the N-terminal region is more abundant while the non-amyloid-β component (NAC) and C-terminal regions show a decrease in β-sheet abundance upon A53T mutation. Obtained results utilizing our new theoretical strategy show that the residual secondary structure conversion stabilities resulting in α-helix formation are not significantly affected by the mutation. Interestingly, the residual secondary structure conversion stabilities show that secondary structure conversions resulting in β-sheet formation are influenced by the A53T mutation and the most stable residual transition yielding β-sheet occurs directly from the coil structure. Long-range interactions detected between the NAC region and the N- or C-terminal regions of the wild-type αS disappear upon A53T mutation. The A53T mutant-type αS structures are thermodynamically more stable than those of the wild-type αS protein structures in aqueous solution. Overall, the higher propensity of the A53T mutant-type αS protein to aggregate in comparison to the wild-type αS protein is related to the increased β-sheet formation and lack of strong intramolecular long-range interactions in the N-terminal region in comparison to its wild-type form. The specific residual secondary structure component s...

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Section: ■ Results and Discussionmentioning

confidence: 99%

Structures and Free Energy Landscapes of the A53T Mutant-Type α-Synuclein Protein and Impact of A53T Mutation on the Structures of the Wild-Type α-Synuclein Protein with Dynamics

Coskuner

Wise-Scira

2013

ACS Chem. Neurosci.

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“…The differences observed both experimentally and computationally between the different distance-range sensitivities may have implications for aggregation of this protein. Much previous work has attempted to discover the preamyloid or aggregation-prone structure with little success (51)(52)(53)(54)(55). We have previously shown that aggregation of aS is correlated with the intramolecular diffusion coefficient, as measured by Trp-Cys quenching, compared to bimolecular diffusion (19,(56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

Intramolecular Diffusion in α-Synuclein: It Depends on How You Measure It

Woodard

Srivastava

Rahamim

et al. 2018

Biophysical Journal

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Intramolecular protein diffusion, the motion of one part of the polypeptide chain relative to another part, is a fundamental aspect of protein folding and may modulate amyloidogenesis of disease-associated intrinsically disordered proteins. Much work has determined such diffusion coefficients using a variety of probes, but there has been an apparent discrepancy between measurements using long-range probes, such as fluorescence resonance energy transfer, and short-range probes, such as Trp-Cys quenching. In this work, we make both such measurements on the same protein, α-synuclein, and confirm that such discrepancy exists. Molecular dynamics simulations suggest that such differences result from a diffusion coefficient that depends on the spatial distance between probes. Diffusional estimates in good quantitative agreement with experiment are obtained by accounting for the distinct distance ranges probed by fluorescence resonance energy transfer and Trp-Cys quenching.

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“…Coskuner and co-workers studied the structure of the WT αS and the impacts of A53T, E46K and A30P pathological missense mutations on the structure of this protein [ 199 , 200 , 201 ]. IDPs can adopt a multitude of different conformations.…”

Section: Artificial and Pathological Mutations In α-Synuclein: Insmentioning

confidence: 99%

Insights into the Molecular Mechanisms of Alzheimer’s and Parkinson’s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology

Coskuner‐Weber

Uversky

2018

IJMS

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Amyloid-β and α-synuclein are intrinsically disordered proteins (IDPs), which are at the center of Alzheimer’s and Parkinson’s disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-β and α-synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer’s and Parkinson’s diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β and α-synuclein in relation to the pathologies of Alzheimer’s and Parkinson’s diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer’s and Parkinson’s diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid-β and α-synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid-β and α-synuclein, such as β-structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer’s and Parkinson’s diseases. This information represents an important foundation for the successful and efficient drug design studies.

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Structures and Free Energy Landscapes of the Wild-Type and A30P Mutant-Type α-Synuclein Proteins with Dynamics

Cited by 34 publications

References 63 publications

Structures and Free Energy Landscapes of the A53T Mutant-Type α-Synuclein Protein and Impact of A53T Mutation on the Structures of the Wild-Type α-Synuclein Protein with Dynamics

Structures and Free Energy Landscapes of the A53T Mutant-Type α-Synuclein Protein and Impact of A53T Mutation on the Structures of the Wild-Type α-Synuclein Protein with Dynamics

Intramolecular Diffusion in α-Synuclein: It Depends on How You Measure It

Insights into the Molecular Mechanisms of Alzheimer’s and Parkinson’s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology

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