Free Energy Landscape of Type III Fibronectin Domain with Identified Intermediate State and Hierarchical Symmetry

Phys Rev Lett. 2023 Nov 24;131(21):218402. doi: 10.1103/PhysRevLett.131.218402.

Abstract

The tenth domain of type III fibronectin (FNIII_{10}) mediates cell adhesion to the extracellular matrix. Despite its structural similarity to immunoglobulin domains, FNIII_{10} exhibits unique unfolding behaviors. We employed magnetic tweezers to investigate the unfolding and folding dynamics of FNIII_{10} under physiological forces (4-50 pN). Our results showed that FNIII_{10} follows a consistent transition pathway with an intermediate state characterized by detached A and G β strands. We determined the folding free energies and all force-dependent transition rates of FNIII_{10} and found that both unfolding rates from the native state to the intermediate state and from the intermediate state to the unfolded state deviate from Bell's model. We constructed a quantitative free energy landscape with well-defined traps and barriers that exhibits a hierarchical symmetrical pattern. Our findings provide a comprehensive understanding of FNIII_{10} conformational dynamics and demonstrate how free energy landscape of multistate biomolecules can be precisely mapped, illuminating the relationship between thermal stability, intermediate states, and folding rates in protein folding.

MeSH terms

  • Fibronectins* / metabolism
  • Mechanical Phenomena
  • Protein Folding*

Substances

  • Fibronectins