Hierarchical nanomechanics of collagen microfibrils

Collagen constitutes one third of the human proteome, providing mechanical stability, elasticity and strength to connective tissues. Collagen is also the dominating material in the extracellular matrix (ECM) and is thus crucial for cell differentiation, growth and pathology. However, fundamental questions remain with respect to the origin of the unique mechanical properties of collagenous tissues, and in particular its stiffness, extensibility and nonlinear mechanical response. By using x-ray diffraction data of a collagen fibril reported by Orgel et al. (Proceedings of the National Academy of Sciences USA, 2006) in combination with protein structure identification methods, here we present an experimentally validated model of the nanomechanics of a collagen microfibril that incorporates the full biochemical details of the amino acid sequence of the constituting molecules. We report the analysis of its mechanical properties under different levels of stress and solvent conditions, using a full-atomistic force field including explicit water solvent. Mechanical testing of hydrated collagen microfibrils yields a Young’s modulus of ≈300 MPa at small and ≈1.2 GPa at larger deformation in excess of 10% strain, in excellent agreement with experimental data. Dehydrated, dry collagen microfibrils show a significantly increased Young’s modulus of ≈1.8 to 2.25 GPa (or ≈6.75 times the modulus in the wet state) owing to a much tighter molecular packing, in good agreement with experimental measurements (where an increase of the modulus by ≈9 times was found). Our model demonstrates that the unique mechanical properties of collagen microfibrils can be explained based on their hierarchical structure, where deformation is mediated through mechanisms that operate at different hierarchical levels. Key mechanisms involve straightening of initially disordered and helically twisted molecules at small strains, followed by axial stretching of molecules, and eventual molecular uncoiling at extreme deformation. These mechanisms explain the striking difference of the modulus of collagen fibrils compared with single molecules, which is found in the range of 4.8±2 GPa or ≈10-20 times greater. These findings corroborate the notion that collagen tissue properties are highly scale dependent and nonlinear elastic, an issue that must be considered in the development of models that describe the interaction of cells with collagen in the extracellular matrix. A key impact the atomistic model of collagen microfibril mechanics reported here is that it enables the bottom-up elucidation of structure-property relationships in the broader class of collagen materials such as tendon or bone, including studies in the context of genetic disease where the incorporation of biochemical, genetic details in material models of connective tissue is essential

Molecular and nanostructural mechanisms of deformation, strength and toughness of spider silk fibrils

Spider silk is one of the strongest, most extensible and toughest biological materials known, exceeding the properties of many engineered materials including steel. Silks feature a hierarchical architecture where highly organized, densely H-bonded beta-sheet nanocrystals are arranged within a semi-amorphous protein matrix consisting of 31-helices and beta-turn protein structures. By using a bottom-up molecular-based mesoscale model that bridges the scales from Angstroms to hundreds of nanometers, here we show that the specific combination of a crystalline phase and a semi-amorphous matrix is crucial for the unique properties of silks. Specifically, our results reveal that the superior mechanical properties of spider silk can be explained solely by structural effects, where the geometric confinement of beta-sheet nanocrystals combined with highly extensible semi-amorphous domains with a large hidden length is the key to reach great strength and great toughness, despite the dominance of mechanically inferior chemical interactions such as H-bonding. Our model directly shows that semi-amorphous regions unravel first when silk is being stretched, leading to the large extensibility of silk. Conversely, the large-deformation mechanical properties and ultimate tensile strength of silk is controlled by the strength of beta-sheet nanocrystals, which is directly related to their size, where small beta-sheet nanocrystals are crucial to reach outstanding levels of strength and toughness. Our model agrees well with observations in recent experiments, where it was shown that a significant change in the strength and toughness can be achieved solely by tuning the size of beta-sheet nanocrystals. Our findings unveil the material design strategy that enables silks to achieve superior material performance despite simple and inferior constituents, resulting in a new paradigm in materials design where enhanced functionality is not achieved using complex building blocks, but rather through the utilization of simple repetitive constitutive elements arranged in hierarchical structures

La asistencia espiritual con los enfermos terminales

La muerte es el destino inevitable de todo ser humano, una etapa en la vida de todos los seres vivos que constituye el horizonte natural del proceso vital. Ésta forma parte de nosotros porque afecta a quienes nos rodean y porque la actitud que adoptamos ante el hecho de que hemos de morir determina en buena medida la manera como vivimos. Pero recordemos que “el moribundo es un viviente”: con estas afirmaciones se abre la reciente publicación ‘Luci nel tramonto’. El autor precisa que el moribundo no es aquél que vive los últimos instantes de la vida, sino una persona que vive la condición característica de una enfermedad incurable, progresiva e irreversible, desde el progresivo deterioramiento y declino de las normales funciones fisiológicas y psíquicas hasta la muerte verdadera. El moribundo es en primer lugar un viviente y como tal requiere ser considerado, acogido y acompañado en cada momento y en cada fase de la relación.Sección: DebatesHospital Interzonal General de Agudos "Prof. Dr. R. Rossi

Nanostructure and stability of calcitonin amyloids

Calcitonin is a 32-amino acid thyroid hormone that can form amyloid fibrils. The structural basis of the fibril formation and stabilization is still debated and poorly understood. The reason is that NMR data strongly suggest antiparallel β-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp15 to Phe19 of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel β-sheets. In this work, we first predict the structure of human calcitonin through two complementary molecular dynamics (MD) methods, finding that human calcitonin forms an α-helix. We use extensive MD simulations to compare previously proposed calcitonin fibril structures. We find that two conformations, the parallel arrangement and one of the possible antiparallel structures (with Asp15 and Phe19 aligned), are highly stable and ordered. Nonetheless, fibrils with parallel molecules show bulky loops formed by residues 1 to 7 located on the same side, which could limit or prevent the formation of larger amyloids. We investigate fibrils formed by the DFNKF peptide by simulating different arrangements of this amyloidogenic core sequence. We show that DFNKF fibrils are highly stable when assembled in parallel β-sheets, whereas they quickly unfold in antiparallel conformation. Our results indicate that the DFNKF peptide represents only partially the full-length calcitonin behavior. Contrary to the full-length polypeptide, in fact, the DFNKF sequence is not stable in antiparallel conformation, suggesting that the residue flanking the amyloidogenic peptide contributes to the stabilization of the experimentally observed antiparallel β-sheet packing

TCT-437 Transcatheter vs surgical mitral annuloplasty: computational analysis of the biomechanical impact

n/

Womersley Number-Based Estimates of Blood Flow Rate in Doppler Analysis: In Vivo Validation by Means of Phase-Contrast MRI

The aim of this paper, was to present an in vivo validation of the Womersley number-based formula, by means of 2-D cine phase-contrast MRI (PCMRI)