title: Comparison of the early stages of forced unfolding for fibronectin type III modules.
abstract: 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.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: D
authors.initials: D
authors.lastname: Craig
authors.forename: A
authors.initials: A
authors.lastname: Krammer
authors.forename: K
authors.initials: K
authors.lastname: Schulten
authors.forename: V
authors.initials: V
authors.lastname: Vogel
mesh_terms: D000595:Amino Acid Sequence; D005353:Fibronectins / Q000737:chemistry*; D006801:Humans; D008969:Molecular Sequence Data; D011489:Protein Denaturation; D017386:Sequence Homology, Amino Acid
chemical_list: D005353:Fibronectins