TY - JOUR
T1 - A kinetic molecular model of the reversible unfolding and refolding of titin under force extension
AU - Zhang, Bo
AU - Xu, Guangzhao
AU - Evans, John Spencer
N1 - Funding Information:
This work was supported by the National Science Foundation (CAREER Award MCB 95-13250; MCB 98-16703), and is contribution number 8 from the Laboratory for Chemical Physics, New York University.
PY - 1999/9
Y1 - 1999/9
N2 - 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 ⇆ T ⇆ 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.
AB - 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 ⇆ T ⇆ 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.
UR - http://www.scopus.com/inward/record.url?scp=0032816936&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032816936&partnerID=8YFLogxK
U2 - 10.1016/S0006-3495(99)76980-8
DO - 10.1016/S0006-3495(99)76980-8
M3 - Article
C2 - 10465743
AN - SCOPUS:0032816936
SN - 0006-3495
VL - 77
SP - 1306
EP - 1315
JO - Biophysical Journal
JF - Biophysical Journal
IS - 3
ER -