Structural and mechanical properties of intermediate filaments under extreme conditions and disease

Abstract

Intermediate filaments are one of the three major components of the cytoskeleton in eukaryotic cells. It was discovered during the recent decades that intermediate filament proteins play key roles to reinforce cells subjected to large-deformation as well as participate in signal transduction. However, it is still poorly understood how the nanoscopic structure, as well as the biochemical properties of these protein molecules contribute to their biomechanical functions. In this research we investigate the material function of intermediate filaments under various extreme mechanical conditions as well as disease states. We use a full atomistic model and study its response to mechanical stresses. Learning from the mechanical response obtained from atomistic simulations, we build mesoscopic models following the finer-trains-coarser principles. By using this multiple-scale model, we present a detailed analysis of the mechanical properties and associated deformation mechanisms of intermediate filament network. We reveal the mechanism of a transition from alpha-helices to beta-sheets with subsequent intermolecular sliding under mechanical force, which has been inferred previously from experimental results. This nanoscale mechanism results in a characteristic nonlinear force-extension curve, which leads to a delocalization of mechanical energy and prevents catastrophic fracture. This explains how intermediate filament can withstand extreme mechanical deformation of >100% strain despite the presence of structural defects. We combine computational and experimental techniques to investigate the molecular mechanism of Hutchinson-Gilford progeria syndrome, a premature aging disease. We find that the mutated domain tail domain is more compact and stable than the normal one. This altered structure and stability may enhance the association of intermediate filaments with the nuclear membrane, providing a molecular mechanism of the disease. We study the nuclear membrane association with intermediate filaments by focusing on the effect of calcium on the maturation process of lamin A. Our result shows that calcium plays a regulatory role in the post-translational processing of lamin A by tuning its molecular conformation and mechanics. Based on these findings we demonstrate that multiple-scale computational modeling provides a useful tool in understanding the biomechanical property and disease mechanism of intermediate filaments. We provide a perspective on research opportunities to improve the foundation for engineering the mechanical and biochemical functions of biomaterials.