The name, "intermediate filaments," was coined back in the 1970s because the diameter of about 10 nm appeared to be intermediate in size between those of myosin thick filaments and actin microfilaments. More recently, the interest in intermediate filaments has increased substantially as it became clear that they are critical to many important cellular functions.
Although intermediate filaments were discovered more than 30 years ago, their molecular-level structure and nanomechanical properties remain elusive. Notably, it is an extremely stretchy filament (that can be stretched to four times its initial length), thereby distinguishing itself noticeably from the other cytoskeletal proteins – the mechanical properties of intermediate filaments play a major role in biology. In fact, researchers have dubbed intermediate filaments the "safety belt of cells" to describe the protein's ability to give strength and support to cells and the nuclear envelope at very large deformation. Indeed, cells without or with much fewer intermediate filaments lose their stretchiness, leading to severe diseases. However, the source of the extreme stretchiness of this protein remains elusive, partly due to our lack of an ability to directly image the molecular structures and mechanisms that define the properties of intermediate filaments.
Bottom-up perspective
Now researchers at the Massachusetts Institute of Technology, US, and Dalhousie University, Canada, have reported studies that for the first time elucidate the properties of vimentin intermediate filaments from a fundamental, molecular bottom-up perspective.
The team has set up a molecular model of an intermediate filament dimer structure – the fundamental building block of intermediate filaments – and investigated its mechanical and structural properties under tensile loading using molecular dynamics simulation. Through a series of simulations with different pulling rates – a strategy that allows the researchers to probe the physical properties of the protein at different time scales of observation – the rate dependence of the rupture force was identified, enabling the group to link the simulation predictions to experimental results, where good agreement between experiment and simulation was found.
Alpha–beta transition
By using the molecular simulation approach as a "computational microscope" to look into the nanoscale mechanisms of deformation, the researchers observed that mechanical stretch induces a transition from alpha-helices to beta-sheets, a phenomenon known as alpha–beta transition. The in silico studies also suggest that the protein's four major domains consistently unfold in a particular sequence that reflects distinct levels of applied stretch, perhaps playing a role in signalling processes in the cell.
This study provides a new way forward in carrying out multiscale studies of structure-property relationships in the intermediate filament protein family, starting from the nanoscale. The use of the new simulation model combined with experimental studies using atomic force microscopy or optical tweezers opens up the possibility for probing the effect of mutations using in silico materiomics methods.
In addition to biomedical applications, intermediate filaments can be considered as a model system that may enable us to fabricate novel nanomaterials. These structures could potentially display a high sensitivity to applied forces, show flaw tolerant properties, provide a rapid route towards self-assembly, and combine biological compatibility with the possibility to achieve multifunctional and mutable material properties.
Such nanomaterials could be used as biomaterials for clinical applications, or as novel efficient energy-absorbing materials. Because the molecular structure of intermediate filaments can be converted to beta-sheets on stretching, bundles of intermediate filaments could potentially be converted into silk-like fibres with a similar strength and toughness as spider silk.
The research is part of a larger effort pursued by the group to understand the role of materials in biology at multiple scales, an effort defined as materiomics. Through these efforts, the long-term goal of the work is to elucidate the mechanical roles of the intermediate filament network and to understand the multiscale effects of mutations from molecular levels to cell levels.
This work was funded by the Air Force Office of Scientific Research (AFOSR) and Natural Sciences and Engineering Research Council of Canada (NSERC).
The researchers presented their work in Nanotechnology.