Dataset Information

Mechanical and thermodynamic properties of A?₄₂, A?₄₀, and ?-synuclein fibrils: a coarse-grained method to complement experimental studies.

ABSTRACT: We perform molecular dynamics simulation on several relevant biological fibrils associated with neurodegenerative diseases such as A?₄₀, A?₄₂, and ?-synuclein systems to obtain a molecular understanding and interpretation of nanomechanical characterization experiments. The computational method is versatile and addresses a new subarea within the mechanical characterization of heterogeneous soft materials. We investigate both the elastic and thermodynamic properties of the biological fibrils in order to substantiate experimental nanomechanical characterization techniques that are quickly developing and reaching dynamic imaging with video rate capabilities. The computational method qualitatively reproduces results of experiments with biological fibrils, validating its use in extrapolation to macroscopic material properties. Our computational techniques can be used for the co-design of new experiments aiming to unveil nanomechanical properties of biological fibrils from a point of view of molecular understanding. Our approach allows a comparison of diverse elastic properties based on different deformations , i.e., tensile (Y _L), shear (S), and indentation (Y _T) deformation. From our analysis, we find a significant elastic anisotropy between axial and transverse directions (i.e., Y _T > Y _L) for all systems. Interestingly, our results indicate a higher mechanostability of A?₄₂ fibrils compared to A?₄₀, suggesting a significant correlation between mechanical stability and aggregation propensity (rate) in amyloid systems. That is, the higher the mechanical stability the faster the fibril formation. Finally, we find that ?-synuclein fibrils are thermally less stable than ?-amyloid fibrils. We anticipate that our molecular-level analysis of the mechanical response under different deformation conditions for the range of fibrils considered here will provide significant insights for the experimental observations.

SUBMITTER: Poma AB

PROVIDER: S-EPMC6404408 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Mechanical and thermodynamic properties of Aβ42, Aβ40, and α-synuclein fibrils: a coarse-grained method to complement experimental studies.

Poma Adolfo B AB Guzman Horacio V HV Li Mai Suan MS Theodorakis Panagiotis E PE

Beilstein journal of nanotechnology 20190219

We perform molecular dynamics simulation on several relevant biological fibrils associated with neurodegenerative diseases such as Aβ40, Aβ42, and α-synuclein systems to obtain a molecular understanding and interpretation of nanomechanical characterization experiments. The computational method is versatile and addresses a new subarea within the mechanical characterization of heterogeneous soft materials. We investigate both the elastic and thermodynamic properties of the bi ...[more]

PMID: 30873322

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Project description:Amyloid fibrils are highly ordered protein aggregates that are associated with several pathological processes, including prion propagation and Alzheimer's disease. A key issue in amyloid science is the need to understand the mechanical properties of amyloid fibrils and fibers to quantify biomechanical interactions with surrounding tissues, and to identify mechanobiological mechanisms associated with changes of material properties as amyloid fibrils grow from nanoscale to microscale structures. Here we report a series of computational studies in which atomistic simulation, elastic network modeling, and finite element simulation are utilized to elucidate the mechanical properties of Alzheimer's Abeta(1-40) amyloid fibrils as a function of the length of the protein filament for both twofold and threefold symmetric amyloid fibrils. We calculate the elastic constants associated with torsional, bending, and tensile deformation as a function of the size of the amyloid fibril, covering fibril lengths ranging from nanometers to micrometers. The resulting Young's moduli are found to be consistent with available experimental measurements obtained from long amyloid fibrils, and predicted to be in the range of 20-31 GPa. Our results show that Abeta(1-40) amyloid fibrils feature a remarkable structural stability and mechanical rigidity for fibrils longer than approximately 100 nm. However, local instabilities that emerge at the ends of short fibrils (on the order of tens of nanometers) reduce their stability and contribute to their disassociation under extreme mechanical or chemical conditions, suggesting that longer amyloid fibrils are more stable. Moreover, we find that amyloids with lengths shorter than the periodicity of their helical pitch, typically between 90 and 130 nm, feature significant size effects of their bending stiffness due the anisotropy in the fibril's cross section. At even smaller lengths (50 nm), shear effects dominate lateral deformation of amyloid fibrils, suggesting that simple Euler-Bernoulli beam models fail to describe the mechanics of amyloid fibrils appropriately. Our studies reveal the importance of size effects in elucidating the mechanical properties of amyloid fibrils. This issue is of great importance for comparing experimental and simulation results, and gaining a general understanding of the biological mechanisms underlying the growth of ectopic amyloid materials.

Project description:We propose a simple general framework to predict folding, native states, energy barriers, protein unfolding, as well as mutation induced diseases and other protein structural analyses. The model should not be considered as an alternative to classical approaches (Molecular Dynamics or Monte Carlo) because it neglects low scale details and rather focuses on global features of proteins and structural information. We aim at the description of phenomena that are out of the range of classical molecular modeling approaches due to the large computational cost: multimolecular interactions, cyclic behavior under variable external interactions, and similar. To demonstrate the effectiveness of the approach in a real case, we focus on the folding and unfolding behavior of tropoelastin and its mutations. Specifically, we derive a discrete mechanical model whose structure is deduced based on a coarse graining approach that allows us to group the amino acids sequence in a smaller number of `equivalent' masses. Nearest neighbor energy terms are then introduced to reproduce the interaction of such amino acid groups. Nearest and non-nearest neighbor energy terms, inter and intra functional blocks are phenomenologically added in the form of Morse potentials. As we show, the resulting system reproduces important properties of the folding-unfolding mechanical response, including the monotonic and cyclic force-elongation behavior, representing a physiologically important information for elastin. The comparison with the experimental behavior of mutated tropoelastin confirms the predictivity of the model. STATEMENT OF SIGNIFICANCE: Classical approaches to the study of phenomena at the molecular scale such as Molecular Dynamics (MD) represent an incredible tool to unveil mechanical and conformational properties of macromolecules, in particular for biological and medical applications. On the other hand, due to the computational cost, the time and spatial scales are limited. Focusing of the real case of tropoelastin, we propose a new approach based on a careful coarse graining of the system, able to describe the overall properties of the macromolecule and amenable of extension to larger scale effects (protein bundles, protein-protein interactions, cyclic loading). The comparison with tropoelastin behavior, also for mutations, is very promising.

Project description:α-Synuclein (α-syn) is a 140 amino acid intrinsically disordered protein (IDP) and the primary component of cytotoxic oligomers implicated in the etiology of Parkinson's disease (PD). While IDPs lack a stable three-dimensional structure, they sample a heterogeneous ensemble of conformations that can, in principle, be assessed through molecular dynamics simulations. However, describing the structure and aggregation of large IDPs is challenging due to force field (FF) accuracy and sampling limitations. To cope with the latter, coarse-grained (CG) FFs emerge as a potential alternative at the expense of atomic detail loss. Whereas CG models can accurately describe the structure of the monomer, less is known about aggregation. The latter is key for assessing aggregation pathways and designing aggregation inhibitor drugs. Herein, we investigate the structure and dynamics of α-syn using different resolution CG (Martini3 and Sirah2) and all-atom (Amber99sb and Charmm36m) FFs to gain insight into the differences and resemblances between these models. The dependence of the magnitude of protein-water interactions and the putative need for enhanced sampling (replica exchange) methods in CG simulations are analyzed to distinguish between force field accuracy and sampling limitations. The stability of the CG models of an α-syn fibril was also investigated. Additionally, α-syn aggregation was studied through umbrella sampling for the CG models and CG/all-atom models for an 11-mer peptide (NACore) from an amyloidogenic domain of α-syn. Our results show that despite the α-syn structures of Martini3 and Sirah2 with enhanced protein-water interactions being similar, major differences exist concerning aggregation. The Martini3 fibril is not stable, and the binding free energy of α-syn and NACore is positive, opposite to Sirah2. Sirah2 peptides in a zwitterionic form, in turn, display termini interactions that are too strong, resulting in end-to-end orientation. Sirah2, with enhanced protein-water interactions and neutral termini, provides, however, a peptide aggregation free energy profile similar to that found with all-atom models. Overall, we find that Sirah2 with enhanced protein-water interactions is suitable for studying protein-protein and protein-drug aggregation.

Dataset Information

Mechanical and thermodynamic properties of A?₄₂, A?₄₀, and ?-synuclein fibrils: a coarse-grained method to complement experimental studies.

Publications

Mechanical and thermodynamic properties of Aβ<sub>42</sub>, Aβ<sub>40</sub>, and α-synuclein fibrils: a coarse-grained method to complement experimental studies.

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Dataset Information

Mechanical and thermodynamic properties of A?42, A?40, and ?-synuclein fibrils: a coarse-grained method to complement experimental studies.

Publications

Mechanical and thermodynamic properties of Aβ<sub>42</sub>, Aβ<sub>40</sub>, and α-synuclein fibrils: a coarse-grained method to complement experimental studies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Mechanical and thermodynamic properties of A?₄₂, A?₄₀, and ?-synuclein fibrils: a coarse-grained method to complement experimental studies.