title: Coiled-coil intermediate filament stutter instability and molecular unfolding.
abstract: Intermediate filaments (IFs) are the key components of cytoskeleton in eukaryotic cells and are critical for cell mechanics. The building block of IFs is a coiled-coil alpha-helical dimer, consisting of several domains that include linkers and other structural discontinuities. One of the discontinuities in the dimer's coiled-coil region is the so-called 'stutter' region. The stutter is a region where a variation of the amino acid sequence pattern from other parts of the alpha-helical domains of the protein is found. It was suggested in earlier works that due to this sequence variation, the perfect coiled-coil arrangement ceases to exist. Here, we show using explicit water molecular dynamics and well-tempered metadynamics that for the coil2 domain of vimentin IFs the stutter is more stable in a non-alpha-helical, unfolded state. This causes a local structural disturbance in the alpha helix, which has a global effect on the nanomechanics of the structure. Our analysis suggests that the stutter features an enhanced tendency to unfolding even under the absence of external forces, implying a much greater structural instability than previously assumed. As a result it features a smaller local bending stiffness than other segments and presents a seed for the initiation of molecular bending and unfolding at large deformation.
authors.affiliation: Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Melis
authors.initials: M
authors.lastname: Arslan
authors.forename: Zhao
authors.initials: Z
authors.lastname: Qin
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Buehler
mesh_terms: D003198:Computer Simulation; D019281:Dimerization; D006801:Humans; D006860:Hydrogen Bonding; D007381:Intermediate Filament Proteins / Q000737:chemistry*; D007382:Intermediate Filaments / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D056811:Unfolded Protein Response; D014746:Vimentin / Q000737:chemistry
chemical_list: D007381:Intermediate Filament Proteins; D014746:Vimentin