Unfolded annealing molecular dynamics conformers for wild-type and disease-associated variants of alpha-synuclein show no propensity for beta-sheetformation

Balesh, Diana; Ramjan, Zack; Floriano, Weley B.

doi:10.4236/jbpc.2011.22015

Cited by 9 publications

(24 citation statements)

References 39 publications

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“…Furthermore, they reported that the average radius of gyration (R g ) of the A53T mutant-type αS protein is larger than that of the wild-type αS for most of the protein ensembles investigated, which is in agreement with our findings (see below). Possible variations in the results reported by Balesh et al 35 and between our studies, which are in agreement with experiments and the results presented by Carloni and co-workers, 36 may occur due to various reasons: the initial structure chosen by Balesh et al is the micelle bound αS structure instead of an extended structure or an experimentally determined free αS conformation; the impact of the confined aqueous volume on the simulations performed by Balesh et al cannot be addressed because the solvation process is not described in detail (volume and number of water molecules are missing); decreasing the temperature to 0 K might influence the reported structures for the body temperature depending on the simulation time. 35 The probability distribution of the R g values for the wild-type and A53T mutant-type αS proteins are presented in Figure 6.…”

Section: ■ Results and Discussionmentioning

confidence: 81%

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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: 81%

“…34 Balesh et al performed classical MD and annealing MD (AMD) simulations of the wild-and mutant-type αS proteins. 35 They reported similar helical and β-sheet contents for the wild-type and A53T mutant-type αS proteins. Furthermore, they presented a more compact structure for the A53T mutant-type αS than the wild-type.…”

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confidence: 91%

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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“…16 Molecular dynamic was also used to vary the stability and structural properties of several α-synuclein oligomers and mutated sequences. [17][18][19][20][21] In this article, we are interested in characterizing the first steps of α-synuclein oligomerization. More precisely, we focus on the 35-residue NAC fragment.…”

Section: Introductionmentioning

confidence: 99%

“…33 Others have focused on the characteristic mutations present in this region. 19,20,34 Yet, there is still very little structural information regarding the onset of oligomerization for the NAC peptide with only rare simulations done to serve as a reference model for experiments. 17 The simulations presented here form therefore a first atomistic description of the onset of oligomerization for the NAC peptide.…”

Section: Introductionmentioning

confidence: 99%

Early oligomerization stages for the non-amyloid component of α-synuclein amyloid

Eugene

Laghaei

Mousseau

2014

The Journal of Chemical Physics

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In recent years, much effort has focused on the early stages of aggregation and the formation of amyloid oligomers. Aggregation processes for these proteins are complex and their non-equilibrium nature makes any experimental study very difficult. Under these conditions, simulations provide a useful alternative for understanding the dynamics of the early stages of oligomerization. Here, we focus on the non-Aβ amyloid component (NAC) of the monomer, dimer, and trimer of α-synuclein, an important 35-residue sequence involved in the aggregation and fibrillation of this protein associated with Parkinson's disease. Using Hamiltonian and temperature replica exchange molecular dynamics simulations combined with the coarse grained Optimized Potential for Efficient peptide structure Prediction potential, we identify the role of the various regions and the secondary structures for the onset of oligomerization. For this sequence, we clearly observe the passage from α-helix to β-sheet, a characteristic transition of amyloid proteins. More precisely, we find that the NAC monomer is highly structured with two α-helical regions, between residues 2-13 and 19-25. As the dimer and trimer form, β-sheet structures between residues 2-14 and 26-34 appear and rapidly structure the system. The resulting conformations are much more structured than similar dimers and trimers of β-amyloid and amylin proteins and yet display a strong polymorphism at these early stages of aggregation. In addition to its inherent experimental interest, comparison with other sequences shows that NAC could be a very useful numerical model for understanding the onset of aggregation.

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“…Annealing molecular dynamics simulations by Balesh et al presented a decrease in α-helix structure in the A30P mutant-type αS protein structures but an increase in the 3 10 -helix abundance and no change in the β-sheet structure formation upon A30P mutation of the wild-type αS. 35 Detailed information about the tertiary structure and conformational free energy landscape differences was not reported. Furthermore, Perlmutter et al demonstrated successfully that the destabilization of the secondary structure around the mutation site in the A30P mutant-type αS decreased interactions with a micelle via MD simulations without the usage of special sampling techniques.…”

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confidence: 99%

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

Wise-Scira¹,

Aloglu²,

Dunn³

et al. 2013

ACS Chem. Neurosci.

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The 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.

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Unfolded annealing molecular dynamics conformers for wild-type and disease-associated variants of alpha-synuclein show no propensity for beta-sheetformation

Cited by 9 publications

References 39 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

Early oligomerization stages for the non-amyloid component of α-synuclein amyloid

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

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