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Section: New Results

Modeling

Mechanics of collective unfolding

Participants : Matthieu Caruel [correspondant] , Jean-Marc Allain [LMS] , Lev Truskinovsky [LMS] .

Mechanically induced unfolding of passive crosslinkers is a fundamental biological phenomenon encountered across the scales from individual macro-molecules to cytoskeletal actin networks. In this work we study a conceptual model of athermal load-induced unfolding and use a minimalistic setting allowing one to emphasize the role of long-range interactions while maintaining full analytical transparency. Our model can be viewed as a description of a parallel bundle of N bistable units confined between two shared rigid backbones that are loaded through a series spring. We show that the ground states in this model correspond to synchronized, single phase configurations where all individual units are either folded or unfolded. We then study the fine structure of the wiggly energy landscape along the reaction coordinate linking the two coherent states and describing the optimal mechanism of cooperative unfolding. Quite remarkably, our study shows the fundamental difference in the size and structure of the folding-unfolding energy barriers in the hard (fixed displacements) and soft (fixed forces) loading devices which persists in the continuum limit. We argue that both, the synchronization and the non-equivalence of the mechanical responses in hard and soft devices, have their origin in the dominance of long-range interactions. We then apply our minimal model to skeletal muscles where the power-stroke in acto-myosin crossbridges can be interpreted as passive folding. A quantitative analysis of the muscle model shows that the relative rigidity of myosin backbone provides the long-range interaction mechanism allowing the system to effectively synchronize the power-stroke in individual crossbridges even in the presence of thermal fluctuations. In view of the prototypical nature of the proposed model, our general conclusions pertain to a variety of other biological systems where elastic interactions are mediated by effective backbones.

Thermodynamical framework for modeling chemical-mechanical coupling in muscle contraction - Formulation and validation

Participants : Matthieu Caruel, Dominique Chapelle [correspondant] , Philippe Moireau.

Muscle contraction occurs at the nanoscale of a hierarchical multi-scale structure with the attachment of so-called cross-bridges within sarcomeres, namely, the creation of chemical bonds between myosin heads and specific sites on actin filaments. A cross-bridge in itself can be seen as a special chemical entity having internal mechanical variables - or degrees of freedom - pertaining to the actual geometric configuration, which implies that the free energy of the cross-bridge - whether in an attached or unattached state - must be made dependent on these internal variables (T.L. Hill, Free Energy Transduction And Biochemical Cycle Kinetics, Dover, 2004). This provides a thermodynamical basis for modeling the complex interplay of chemical and mechanical phenomena at the sarcomere level. Within this framework we propose a muscle model with two mechanical variables associated with a cross-bridge. For the action of individual cross-bridges occurring at the nanometer scale, the energy provided by the Langevin thermostat cannot be neglected, and we therefore propose to endow the internal mechanical variables with stochastic dynamics. Important motivations for this modeling choice include the ability to represent (i) the so-called power-stroke phenomenon and (ii) short-time responses of a muscle, e.g. to load steps. Our approach allows for systematic treatment of the model energetics, and in particular one goal of the proposed description is to investigate the potential benefit in mechanical efficiency with systems including - in addition to chemically-induced transformations - thermally-induced conformational changes such as the power-stroke.

Mechanical modeling and numerical methods for poromechanics: Applications to cardiac perfusion

Participants : Bruno Burtschell, Dominique Chapelle [correspondant] , Philippe Moireau.

We have previously formulated a rather general modeling framework of poromechanics – formulations that combine solid and fluid components to represent the behavior of a porous medium – to take into account large deformations and rapid fluid flows, see [16] . This allows to consider, in particular, the application of blood perfusion within the cardiac tissue, which features these specific complex phenomena, out of the scope of classical poromechanical models. One of our major objectives now, within the PhD of Bruno Burtschell, is to propose and assess some associated relevant numerical schemes.

Some existing algorithms of fluid-structure interaction, with which our poromechanics formulations feature deep similarities, have been implemented – in FreeFEM++, both in axisymmetric configuration and in 3D – and compared. Their numerical and theoretical analysis – consistency, convergence – has been performed. Then, the adaptation of these algorithms to our poromechanics formulations enabled us to propose a time discretisation well-fitted to our framework, and to present its energy stability analysis. Further perspectives include implementation and numerical validation of this scheme, including special care regarding space discretisation, then integration into FELISCE (“HappyHeart” module).

Personalized modeling for cardiac amyloidosis diagnosis

Participants : Alessandro Felder, Dominique Chapelle, Philippe Moireau, Jean-François Deux [Hôpital Henri Mondor] , Thibault Damy [Hôpital Henri Mondor] .

Cardiac amyloidosis is a condition induced by pathological deposition of amyloid proteins within muscle tissue and nerves, thus severely impairing the cardiac function and often requiring cardiac transplantation as the only available treatment. Our objective here in a first stage is to use our previously developed patient-specific modeling methodologies to analyse some clinical cases – based on actual patient data – to better apprehend the impact of the pathology on biomechanical properties. Further perspectives include the modeling of the protein deposition and associated tissue remodeling in order to predict the disease evolution in a patient-specific context. This work is performed in collaboration with medical doctors from Hôpital Henri Mondor (Créteil).