Computational and theoretical modeling of intermediate filament networks:Structure,mechanics and disease

Intermediate filaments, in addition to microtubules and actin microfilaments, are one of the three major components of the cytoskeleton in eukaryotic cells. It was discovered during the recent decades that in most cells, intermediate filament proteins play key roles to reinforce cells subjected to large-deformation, and that they participate in signal transduction, and it was proposed that their nanome- chanical properties are critical to perform those functions. However, it is still poorly understood how the nanoscopic structure, as well as the combination of chemical composition, molecular structure and interfacial properties of these protein molecules contribute to the biomechanical properties of filaments and filament networks. Here we review recent progress in computational and theoretical studies of the intermediate filaments network at various levels in the protein＇s structure. A multiple scale method is discussed, used to couple molecular modeling with atomistic detail to larger-scale material properties of the networked material. It is shown that a finer-trains-coarser method- ology as discussed here provides a useful tool in understanding the biomechanical property and disease mechanism of intermediate filaments, coupling experiment and simulation. It further allows us to improve the understanding of associated disease mechanisms and lays the foundation for engineering the mechanical properties of biomaterials.

Compressive deformation of ultralong amyloid fibrils

Involved in various neurodegenerative diseases, amyloid fibrils and plaques feature a hierarchical structure, ranging from the atomistic to the micrometer scale.At the atomistic level,a dense and organized hydrogen bond network is resembled in a beta-sheet rich secondary structure, which drives a remarkable stiffness in the range of 10-20GPa,larger than many other biological nanofibrils, a result confirmed by both experiment and theory.However, the understanding of how these exceptional mechanical properties transfer from the atomistic to the nanoscale remains unknown.Here we report a multiscale analysis that, from the atomistic-level structure of a single fibril,extends to the mesoscale level,reaching size scales of hundreds of nanometers.We use parameters directly derived from full atomistic simulations of Aβ（1-40） amyloid fibrils to parameterize a mesoscopic coarse-grained model,which is used to reproduce the elastic properties of amyloid fibrils.We then apply our mesoscopic model in an analysis of the buckling behavior of amyloid fibrils with different lengths and report a comparison with predictions from continuum beam theory. An important implication of our results is a severe reduction of the effective modulus due to buckling,an effect that could be important to interpret experimental results of ultralong amyloid fibrils.Our model represents a powerful tool to mechanically characterize molecular structures on the order of hundreds of nanometers to micrometers on the basis of the underlying atomistic behavior.The work provides insight into structural and mechanical properties of amyloid fibrils and may enable further analysis of larger-scale assemblies such as amyloidogenic bundles or plaques as found in disease states.

Designing architected materials for mechanical compression via simulation, deep learning, and experimentation

Architected materials can achieve enhanced properties compared to their plain counterparts.Specific architecting serves as a powerful design lever to achieve targeted behavior without changing the base material.Thus,the connection between architected structure and resultant properties remains an open field of great interest to many fields,from aerospace to civil to automotive applications.Here,we focus on properties related to mechanical compression,and design hierarchical honeycomb structures to meet specific values of stiffness and compressive stress.To do so,we employ a combination of techniques in a singular workflow,starting with molecular dynamics simulation of the forward design problem,augmenting with data-driven artificial intelligence models to address the inverse design problem,and verifying the behavior of de novo structures with experimentation of additively manufactured samples.We thereby demonstrate an approach for architected design that is generalizable to multiple material properties and agnostic to the identity of the base material.

MULTISCALE MECHANICS OF BIOLOGICAL AND BIOLOGICALLY INSPIRED MATERIALS AND STRUCTURES

The world of natural materials and structures provides an abundance of applications in which mechanics is a critical issue for our understanding of functional material properties. In particular, the mechanical properties of biological materials and structures play an important role in virtually all physiological processes and at all scales, from the molecular and nanoscale to the macroscale, linking research fields as diverse as genetics to structural mechanics in an approach referred to as materiomics. Example cases that illustrate the importance of mechanics in biology include mechanical support provided by materials like bone, the facilitation of locomotion capabilities by muscle and tendon, or the protection against environmental impact by materials as the skin or armors. In this article we review recent progress and case studies, relevant for a variety of applications that range from medicine to civil engineering. We demonstrate the importance of fundamental mechanistic insight at multiple time- and length-scales to arrive at a systematic understanding of materials and structures in biology, in the context of both physiological and disease states and for the development of de novo biomaterials. Three particularly intriguing issues that will be discussed here include： First, the capacity of biological systems to turn weakness to strength through the utilization of multiple structural levels within the universality-diversity paradigm. Second, material breakdown in extreme and disease conditions. And third, we review an example where the hierarchical design paradigm found in natural protein materials has been applied in the development of a novel hiomaterial based on amyloid protein.

Mechanical properties of crosslinks controls failure mechanism of hierarchical intermediate filament networks

Intermediate filaments are one of the key components of the cytoskeleton in eukaryotic cells, and their mechanical properties are found to be equally important for physiological function and disease. While the mechanical properties of single full length filaments have been studied, how the mechanical properties of crosslinks affect the mechanical property of the intermediate filament network is not well understood. This paper applies a mesoscopic model of the intermediate network with varied crosslink strengths to investigate its failure mechanism under the extreme mechanical loading. It finds that relatively weaker crosslinks lead to a more flaw tolerant intermediate filament network that is also 23% stronger than the one with strong crosslinks. These findings suggest that the mechanical properties of interfacial components are critical for bioinspired designs which provide intriguing mechanical properties.

Elasticity,Strength and Resilience:A Comparative Study on Mechanical Signatures ofα-Helix,β-Sheet and Tropocollagen Domains

In biology,structural design and materials engineering is unified through formation of hierarchical features with atomic resolution,from nano to macro.Three molecular building blocks are particularly prevalent in all structural protein materials:alpha helices(AHs),beta-sheets(BSs)and tropocollagen(TC).In this article we present a comparative study of these three key building blocks by focusing on their mechanical signatures,based on results from full-atomistic simulation studies.We fi nd that each of the basic structures is associated with a characteristic material behavior:AH protein domains provide resilience at large deformation through energy dissipation at low force levels,BS protein domains provide great strength under shear loading,and tropocollagen molecules provide large elasticity for deformation recovery.This suggests that AHs,BSs,and TC molecules have mutually exclusive mechanical signatures.We correlate each of these basic properties with the molecule’s structure and the associated fundamental rupture mechanisms.Our study may enable the use of abundant protein building blocks in nanoengineered materials,and may provide critical insight into basic biological mechanisms for bio-inspired nanotechnologies.The transfer towards the design of novel nanostructures could lead to new multifunctional and mechanically active,tunable,and changeable materials.

Linking atomic structural defects to mesoscale properties in crystalline solids using graph neural networks

Structural defects are abundant in solids,and vital to the macroscopic materials properties.However,a defect-property linkage typically requires significant efforts from experiments or simulations,and often contains limited information due to the breadth of nanoscopic design space.Here we report a graph neural network(GNN)-based approach to achieve direct translation between mesoscale crystalline structures and atom-level properties,emphasizing the effects of structural defects.Our end-to-end method offers great performance and generality in predicting both atomic stress and potential energy of multiple systems with different defects.Furthermore,the approach also precisely captures derivative properties which strictly observe physical laws and reproduces evolution of properties with varying boundary conditions.By incorporating a genetic algorithm,we then design de novo atomic structures with optimum global properties and target local patterns.The method would significantly enhance the efficiency of evaluating atomic behaviors given structural imperfections and accelerates the design process at the meso-level.