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ABSTRACT: Vimentin coiled-coil alpha-helical dimers are elementary protein building blocks of intermediate filaments, an important component
of the cell’s cytoskeleton. All intermediate filament dimers feature a highly conserved ‘stutter’ region, a sequence of amino
acids that interrupts the superhelical coiled-coil arrangement of the two alpha-helices, leading to a parallel arrangement
of the alpha-helices in this region. Earlier studies have suggested that the stutter plays an important role in filament assembly.
Here we show that the stutter also has a significant effect on the mechanical behavior of vimentin dimers. We develop an Extended
Bell Model to provide a theoretical description of the unfolding behavior of coiled-coil structures, capable of capturing
different molecular geometries and loading rates. The Extended Bell Model predicts that the stutter represents a molecular
defect at which unfolding occurs at lower forces than in the rest of the protein. Our studies suggest that the presence of
the stutter leads to a softer structure with more homogeneous plastic strain distribution under deformation. The predictions
by the Extended Bell Model are confirmed by large-scale MD simulations of three model systems: Two parallel alpha-helices,
a coiled-coil dimer, as well as a coiled-coil dimer with a stutter. The simulations prove that in agreement with the prediction
based on our Extended Bell Model, the stutter represents the locations at which the protein structure has the least resistance
to unfolding. We discuss the implications of this molecular architecture in terms of its biological function.
Experimental Mechanics 04/2012; 49(1):79-89. · 1.52 Impact Factor
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ABSTRACT: Vimentin coiled-coil alpha-helical dimers are elementary protein building blocks of intermediate filaments, an important component
of the cell’s cytoskeleton that has been shown to control the large-deformation behavior of eukaryotic cells. Here we use
a combination of atomistic simulation and continuum theory to model tensile and bending deformation of single alpha-helices
as well as coiled-coil double helices of the 2B segment of the vimentin dimer. We find that vimentin dimers can be extended
to tensile strains up to 100% at forces below 50pN, until strain hardening sets in with rapidly rising forces, approaching
8nN at 200% strain. We systematically explore the differences between single alpha-helical structures and coiled-coil superhelical
structures. Based on atomistic simulation, we discover a transition in deformation mechanism under varying pulling rates,
resulting in different strength criteria for the unfolding force. Based on an extension of Bell’s theory that describes the
dependence of the mechanical unfolding force on the pulling rate, we develop a fully atomistically informed continuum model
of the mechanical properties of vimentin coiled-coils that is capable of predicting its nanomechanical behavior over a wide
range of deformation rates that include experimental conditions. This model enables us to describe the mechanics of cyclic
stretching experiments, suggesting a hysteresis in the force–strain response, leading to energy dissipation as the protein
undergoes repeated tensile loading. We find that the dissipated energy increases continuously with increasing pulling rate.
Our atomistic and continuum results help to interpret experimental studies that have provided evidence for the significnificance
of vimentin intermediate filaments for the large-deformation regime of eukaryotic cells. We conclude that vimentin dimers
are superelastic, highly dissipative protein assemblies.
Journal of Materials Science 04/2012; 42(21):8771-8787. · 2.02 Impact Factor
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ABSTRACT: Multi-scale properties of biological protein materials have been the focal point of extensive investigations over the past
decades, leading to formation of a research field that connects biology and materials science, referred to as materiomics.
In this chapter we review atomistic based modeling approaches applied to study the scale-dependent mechanical behavior of
biological protein materials, focused on mechanical deformation and failure properties. Specific examples are provided to
illustrate the application of numerical methods that link atomistic to mesoscopic and larger continuum scales. The discussion
includes the formulation of atomistic simulation methods, as well as examples that demonstrate their application in case studies
focused on size effects of the fracture behavior of protein materials. The link of atomistic scale features of molecular structures
to structural scales at length-scales of micrometers will be discussed in the analysis of the mechanics of a simple model
of the nuclear lamin network, revealing how protein networks with structural flaws cope with mechanical load
KeywordsHierarchical material- Nanomechanics- Biological protein materials- Fracture-Deformation-Experiment-Simulation-Materiomics-Multi-scale modeling
03/2010: pages 473-533;
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ABSTRACT: An abundant trait of biological protein materials are hierarchical nanostructures, ranging through atomistic, molecular to macroscopic scales. By utilizing the recently developed Hierarchical Bell Model, here we show that the use of hierarchical structures leads to an extended physical dimension in the material design space that resolves the conflict between disparate material properties such as strength and robustness, a limitation faced by many synthetic materials. We report materiomics studies in which we combine a large number of alpha-helical elements in all possible hierarchical combinations and measure their performance in the strength-robustness space while keeping the total material use constant. We find that for a large number of constitutive elements, most random struc-tural combinations of elements (> 98%) lead to either high strength or high robustness, reflecting the so-called banana-curve performance in which strength and robustness are mutually exclusive properties. This banana-curve type behavior is common to most engi-neered materials. In contrast, for few, very specific types of combinations of the elements in hierarchies (< 2%) it is possible to maintain high strength at high robustness levels. This behavior is reminiscent of naturally observed material performance in biological materials, suggesting that the existence of particular hierarchical structures facilitates a fundamental change of the material performance. The results suggest that biological materials may have developed under evolutionary pressure to yield materials with multi-ple objectives, such as high strength and high robustness, a trait that can be achieved by Corresponding author.
International Journal of Applied Mechanics 04/2009; 15(1):85-112. · 1.16 Impact Factor
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ABSTRACT: Hierarchical nanostructures, ranging through atomistic, molecular and macroscopic scales, represent universal features of biological protein materials. Here we show for the case of alpha-helical (AH) protein domains that this use of molecular hierarchies within the structural arrangement leads to an extended physical dimension in the material design space that resolves the conflict between disparate material properties such as strength and robustness, a limitation faced by many synthetic materials. An optimal combination of redundancies at different hierarchical levels enables superior mechanical performance without additional material use. Our analysis is facilitated by the application of a Hierarchical Bell model (HBM), which explicitly considers the hierarchical architecture of H-bonds within the protein structure, providing a structure-property relationship of strength properties of AH protein nanostructures. The HBM is validated by large-scale molecular dynamics simulations of several model protein structures. Our findings may enable the development of self-assembled de novo bioinspired nanomaterials based on peptide and protein building blocks, and could help in elucidating the mechanistic role of AHs in cell signaling and mechanotransduction.
Nanotechnology 03/2009; 20(7):075103. · 3.98 Impact Factor
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ABSTRACT: Alpha-helix based protein networks as they appear in intermediate filaments in the cell's cytoskeleton and the nuclear membrane robustly withstand large deformation of up to several hundred percent strain, despite the presence of structural imperfections or flaws. This performance is not achieved by most synthetic materials, which typically fail at much smaller deformation and show a great sensitivity to the existence of structural flaws. Here we report a series of molecular dynamics simulations with a simple coarse-grained multi-scale model of alpha-helical protein domains, explaining the structural and mechanistic basis for this observed behavior. We find that the characteristic properties of alpha-helix based protein networks are due to the particular nanomechanical properties of their protein constituents, enabling the formation of large dissipative yield regions around structural flaws, effectively protecting the protein network against catastrophic failure. We show that the key for these self protecting properties is a geometric transformation of the crack shape that significantly reduces the stress concentration at corners. Specifically, our analysis demonstrates that the failure strain of alpha-helix based protein networks is insensitive to the presence of structural flaws in the protein network, only marginally affecting their overall strength. Our findings may help to explain the ability of cells to undergo large deformation without catastrophic failure while providing significant mechanical resistance.
PLoS ONE 02/2009; 4(6):e6015. · 4.09 Impact Factor
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ABSTRACT: Here we report a constitutive model that characterizes the strength of an alpha-helical protein domain subjected to tensile deformation, covering more than ten orders of magnitude in timescales. The model elucidates multiple physical mechanisms of failure in dependence on the deformation rate, quantitatively linking atomistic simulation results with experimental strength measurements of alpha-helical protein domains. The model provides a description of the strength of alpha-helices based on fundamental physical parameters such as the H-bond energy and the polypeptide's persistence length, showing that strength is controlled by energetic, nonequilibrium processes at high rates and by thermodynamical, equilibrium processes at low rates. Our model provides a novel perspective on the strength of protein domains at ultra-slow pulling speeds relevant under physiologic and experimental conditions.
Journal of Physics Condensed Matter 01/2009; 21(3):035111. · 2.55 Impact Factor
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ABSTRACT: Biological protein materials (BPMs), intriguing hierarchical structures formed by assembly of chemical building blocks, are crucial for critical functions of life. The structural details of BPMs are fascinating: They represent a combination of universally found motifs such as alpha-helices or beta-sheets with highly adapted protein structures such as cytoskeletal networks or spider silk nanocomposites. BPMs combine properties like strength and robustness, self-healing ability, adaptability, changeability, evolvability and others into multi-functional materials at a level unmatched in synthetic materials. The ability to achieve these properties depends critically on the particular traits of these materials, first and foremost their hierarchical architecture and seamless integration of material and structure, from nano to macro. Here, we provide a brief review of this field and outline new research directions, along with a review of recent research results in the development of structure-property relationships of biological protein materials exemplified in a study of vimentin intermediate filaments.
Computer Methods in Biomechanics and Biomedical Engineering 10/2008; 11(6):595-607. · 0.85 Impact Factor
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ABSTRACT: Proteins constitute the elementary building blocks of a vast variety of biological materials such as cells, spider silk or bone, where they create extremely robust, multi-functional materials by self-organization of structures over many length- and time scales, from nano to macro. Some of the structural features are commonly found in a many different tissues, that is, they are highly conserved. Examples of such universal building blocks include alpha-helices, beta-sheets or tropocollagen molecules. In contrast, other features are highly specific to tissue types, such as particular filament assemblies, beta-sheet nanocrystals in spider silk or tendon fascicles. These examples illustrate that the coexistence of universality and diversity—in the following referred to as the universality-diversity paradigm (UDP)—is an overarching feature in protein materials. This paradigm is a paradox: How can a structure be universal and diverse at the same time? In protein materials, the coexistence of universality and diversity is enabled by utilizing hierarchies, which serve as an additional dimension, enlarging the 3D or 4D physical space. This may be crucial to understand how their structure and properties are linked, and how these materials are capable of combining seemingly disparate properties such as strength and robustness. Here we illustrate how the UDP enables to unify universal building blocks and highly diversified patterns through formation of hierarchical structures that lead to multi-functional, robust yet highly adapted structures. We illustrate these concepts in an analysis of three types of intermediate filament proteins, including vimentin, lamin and keratin. We provide a perspective on research opportunities and challenges in a variety of disciplines, including an outlook to structural engineering and design of biomimetic nanomaterials.
Journal of Computational and Theoretical Nanoscience 06/2008; 5(7):1193-1204. · 0.91 Impact Factor
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ABSTRACT: Lamin intermediate filaments at the inner nuclear membrane play a key role in mechanosensation and gene regulation processes, and further guarantee the mechanical stability of the cell's nucleus. The rod-like dimers are the elementary building blocks within the dense lamina meshwork, mainly consisting of four alpha-helical coiled-coil segments as fundamental building blocks. Several mutations in the 2B segment of the rod domain of lamin A have been linked to the disease muscle dystrophy. In these diseases, the cell nuclei have been shown to feature abnormalities in the shape and its mechanical properties, leading to torn nuclear envelopes or bleb formation. However, up to now the origin of these mechanical changes remains unknown, in particular whether or not the mutations in the rod domain influence the mechanical properties of individual dimers, or if the changes are due to effects at larger hierarchical scales. Here we report a series of large-scale molecular dynamics studies of lamin A dimer segments, systematically comparing the mechanical behavior of the wild-type protein structure and a missense mutated protein structure with the point mutation p.Glu358Lys. Our results show that the nanomechanical tensile behavior of the dimer segment does not vary under presence of this mutation, suggesting that this single point mutation in muscle dystrophy does not affect the mechanical properties of lamin at the dimer level, but probably influences higher hierarchical scales.
Journal of Biomechanics 02/2008; 41(6):1295-301. · 2.43 Impact Factor
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ABSTRACT: The fundamental fracture mechanisms of biological protein materials remain largely unknown, in part, because of a lack of understanding of how individual protein building blocks respond to mechanical load. For instance, it remains controversial whether the free energy landscape of the unfolding behavior of proteins consists of multiple, discrete transition states or the location of the transition state changes continuously with the pulling velocity. This lack in understanding has thus far prevented us from developing predictive strength models of protein materials. Here, we report direct atomistic simulation that over four orders of magnitude in time scales of the unfolding behavior of alpha-helical (AH) and beta-sheet (BS) domains, the key building blocks of hair, hoof, and wool as well as spider silk, amyloids, and titin. We find that two discrete transition states corresponding to two fracture mechanisms exist. Whereas the unfolding mechanism at fast pulling rates is sequential rupture of individual hydrogen bonds (HBs), unfolding at slow pulling rates proceeds by simultaneous rupture of several HBs. We derive the hierarchical Bell model, a theory that explicitly considers the hierarchical architecture of proteins, providing a rigorous structure-property relationship. We exemplify our model in a study of AHs, and show that 3-4 parallel HBs per turn are favorable in light of the protein's mechanical and thermodynamical stability, in agreement with experimental findings that AHs feature 3.6 HBs per turn. Our results provide evidence that the molecular structure of AHs maximizes its robustness at minimal use of building materials.
Proceedings of the National Academy of Sciences 11/2007; 104(42):16410-5. · 9.68 Impact Factor
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ABSTRACT: Coiled-coil alpha-helical dimers are the elementary building blocks of intermediate filaments (IFs), an important component of the cell's cytoskeleton. Therefore, IFs play a leading role in the mechanical integrity of the cells. Here we use atomistic simulation to carry out tensile tests on coiled-coils as well as on single alpha-helices of the 2B segment of the vimentin dimer that has been shown to control the large-deformation behavior of cells. We compare the characteristic force-strain curves of both structures and suggest explanations for the differences on this fundamental level of hierarchical assembly. We further systematically explore the strain rate dependence of the mechanical properties of the vimentin coiled-coil protein. We develop a simple continuum model capable of reproducing the atomistic modeling results. The model enables us to extrapolate to much lower deformation rates approaching those used in experiment.
MRS Proceedings. 12/2005; 978.
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ABSTRACT: Proteins constitute the elementary building blocks of a vast variety of biological materials such as cellular protein networks, spider silk or bone, where they create extremely robust, multi-functional materials by self-organization of structures over many length- and time scales, from nano to macro. Some of the structural features are commonly found in a many different tissues, that is, they are highly conserved. Examples of such universal building blocks include alpha-helices, beta-sheets or tropocollagen molecules. In contrast, other features are highly specific to tissue types, such as particular filament assemblies, beta-sheet nanocrystals in spider silk or tendon fascicles. These examples illustrate that the coexistence of universality and diversity – in the following referred to as the universality-diversity paradigm (UDP) – is an overarching feature in protein materials. This paradigm is a paradox: How can a structure be universal and diverse at the same time? In protein materials, the coexistence of universality and diversity is enabled by utilizing hierarchies, which serve as an additional dimension beyond the 3D or 4D physical space. This may be crucial to understand how their structure and properties are linked, and how these materials are capable of combining seemingly disparate properties such as strength and robustness. Here we illustrate how the UDP enables to unify universal building blocks and highly diversified patterns through formation of hierarchical structures that lead to multi-functional, robust yet highly adapted structures. We illustrate these concepts in an analysis of three types of intermediate filament proteins, including vimentin, lamin and keratin.
Nature Precedings.
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[show abstract]
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ABSTRACT: Alpha-helix based protein networks as they appear in intermediate filaments in the cell’s cytoskeleton and the nuclear membrane robustly withstand large deformation of up to several hundred percent strain, despite the presence of structural imperfections or flaws. This performance is not achieved by most synthetic materials, which typically fail at much smaller deformation and show a great sensitivity to the existence of structural flaws. Here we report a series of molecular dynamics simulations with a simple coarse-grained multi-scale model of alpha-helical protein domains, explaining the structural and mechanistic basis for this observed behavior. We find that the characteristic properties of alpha-helix based protein networks are due to the particular nanomechanical properties of their protein constituents, enabling the formation of large dissipative yield regions around structural flaws, effectively protecting the protein network against catastrophic failure. We show that the key for these self protecting properties is a geometric transformation of the crack shape that significantly reduces the stress concentration at corners. Specifically, our analysis demonstrates that the failure strain of alpha-helix based protein networks is insensitive to the presence of structural flaws in the protein network, only marginally affecting their overall strength. Our findings may help to explain the ability of cells to undergo large deformation without catastrophic failure while providing significant mechanical resistance. United States Army Research Office (grant number W911NF-06-1-0291) United States Air Force Office of Scientific Research (grant number FA9550-08-1-0321) National Science Foundation (grant number CMMI-0642545)
PLoS.
