Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 10, Pages 5590-5595Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.101582198
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Funding
- NCRR NIH HHS [P41 RR005969, 5 P41 RR05969] Funding Source: Medline
- NIGMS NIH HHS [T32 GM008268, 5 T32 GM08268, R01 GM49063-07, R01 GM60946-01] Funding Source: Medline
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The structural changes accompanying stretch-induced early unfolding events were investigated for the four type III fibronectin (FN-III) modules, FN-III7, FN-IIIg, FN-III9, and FN-III10 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-III7 and lowest for FN-III10. 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-III10, for example, extends 12 Angstrom from the native twisted to the intermediate aligned state, and an additional 10 Angstrom 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
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