Key result
Three-state protein-folding model including PEVK domains accurately reproduces experimental force-extension curves for titin and tenascin.
A kinetic molecular model accurately simulates the unfolding and refolding of titin under force extension, highlighting the role of PEVK domains as a force buffer.
Refines titin force-buffering models in vitro; leaves open validation in cardiac sarcomeres or disease states.
Molecular elasticity is a physicomechanical property that is associated with a select number of polypeptides and proteins, such as the giant muscle protein, titin, and the extracellular matrix protein, tenascin. Both proteins have been the subject of atomic force microscopy (AFM), laser tweezer, and other in vitro methods for examining the effects of force extension on the globular (FNIII/Ig-like) domains that comprise each protein. In this report we present a time-dependent method for simulating AFM force extension and its effect on FNIII/Ig domain unfolding and refolding. This method treats the unfolding and refolding process as a standard three-state protein folding model (U right arrow over left arrow T right arrow over left arrow F, where U is the unfolded state, T is the transition or intermediate state, and F is the fully folded state), and integrates this approach within the wormlike chain (WLC) concept. We simulated the effect of AFM tip extension on a hypothetical titin molecule comprised of 30 globular domains (Ig or FNIII) and 25% Pro-Glu-Val-Lys (PEVK) content, and analyzed the unfolding and refolding processes as a function of AFM tip extension, extension rate, and variation in PEVK content. In general, we find that the use of a three-state protein-folding kinetic-based model and the implicit inclusion of PEVK domains can accurately reproduce the experimental force-extension curves observed for both titin and tenascin proteins. Furthermore, our simulation data indicate that PEVK domains exhibit extensibility behavior, assist in the unfolding and refolding of FNIII/Ig domains in the titin molecule, and act as a force "buffer" for the FNIII/Ig domains, particularly at low and moderate extension forces.
No takes yet. Share an insight, caveat, or question.
Zhang et al. (1999) studied this question. AFM tip extension simulation was evaluated on Unfolding and refolding processes as a function of AFM tip extension, extension rate, and variation in PEVK content. A three-state protein-folding kinetic-based model with implicit inclusion of PEVK domains accurately reproduced experimental force-extension curves for titin and tenascin proteins.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: