Open AccessComparison of the early stages of forced unfolding for fibronectin type III modules
Author(s) -
David W. Craig,
André Krammer,
Klaus Schulten,
Viola Vogel
Publication year - 2001
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.101582198
Subject(s) - crystallography , intermediate state , fibronectin , beta (programming language) , hydrogen bond , molecular dynamics , chemistry , cluster (spacecraft) , molecule , physics , biophysics , materials science , atomic physics , computational chemistry , biology , extracellular matrix , biochemistry , organic chemistry , computer science , programming language
The structural changes accompanying stretch-induced early unfolding events were investigated for the four type III fibronectin (FN-III) modules, FN-III(7), FN-III(8), FN-III(9), and FN-III(10) by using steered molecular dynamics. Simulations revealed that two main energy barriers, I and II, have to be overcome to initiate unraveling of FN-III's tertiary structure. In crossing the first barrier, the two opposing beta-sheets of FN-III are rotated against each other such that the beta-strands of both beta-sheets align parallel to the force vector (aligned state). All further events in the unfolding pathway proceed from this intermediate state. A second energy barrier has to be overcome to break the first major cluster of hydrogen bonds between adjacent beta-strands. Simulations revealed that the height of barrier I varied significantly among the four modules studied, being largest for FN-III(7) and lowest for FN-III(10), whereas the height of barrier II showed little variation. Key residues affecting the mechanical stability of FN-III modules were identified. These results suggest that FN-III modules can be prestretched into an intermediate state with only minor changes to their tertiary structures. FN-III(10), for example, extends 12 A from the native "twisted" to the intermediate aligned state, and an additional 10 A from the aligned state to further unfolding where the first beta-strand is peeled away. The implications of the existence of intermediate states regarding the elasticity of fibrillar fibers and the stretch-induced exposure of cryptic sites are discussed.