Molecular level detection and localization of mechanical damage in collagen enabled by collagen hybridizing peptides.
Mechanical injury to connective tissue causes changes in collagen structure and material behaviour, but the role and mechanisms of molecular damage have not been established. In the case of mechanical subfailure damage, no apparent macroscale damage can be detected, yet this damage initiates and potentiates in pathological processes. Here, we utilize collagen hybridizing peptide (CHP), which binds unfolded collagen by triple helix formation, to detect molecular level subfailure damage to collagen in mechanically stretched rat tail tendon fascicle. Our results directly reveal that collagen triple helix unfolding occurs during tensile loading of collagenous tissues and thus is an important damage mechanism. Steered molecular dynamics simulations suggest that a likely mechanism for triple helix unfolding is intermolecular shearing of collagen α-chains. Our results elucidate a probable molecular failure mechanism associated with subfailure injuries, and demonstrate the potential of CHP targeting for diagnosis, treatment and monitoring of tissue disease and injury.
Department of Bioengineering, University of Utah, Salt Lake City, Utah 84112, USA.|Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, Utah 84112, USA.
Jared L
JL
Zitnay
Department of Bioengineering, University of Utah, Salt Lake City, Utah 84112, USA.
Yang
Y
Li
Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Zhao
Z
Qin
Department of Bioengineering, University of Utah, Salt Lake City, Utah 84112, USA.
Boi Hoa
0000-0001-5340-4920
BH
San
Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Baptiste
0000-0002-5789-0636
B
Depalle
Department of Bioengineering, University of Utah, Salt Lake City, Utah 84112, USA.|Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, Utah 84112, USA.
Shawn P
SP
Reese
Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Markus J
MJ
Buehler
Department of Bioengineering, University of Utah, Salt Lake City, Utah 84112, USA.|Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.
S Michael
SM
Yu
Department of Bioengineering, University of Utah, Salt Lake City, Utah 84112, USA.|Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, Utah 84112, USA.|Department of Orthopedics, University of Utah, Salt Lake City, Utah 84108, USA.
Jeffrey A
JA
Weiss
D000818:Animals; D003094:Collagen / Q000032:analysis* / Q000737:chemistry / Q000502:physiology; D046529:Microscopy, Electron, Transmission; D056004:Molecular Dynamics Simulation; D053758:Nanoparticles / Q000737:chemistry; D010455:Peptides; D058767:Protein Unfolding; D051381:Rats; D013708:Tendon Injuries / Q000473:pathology*; D013710:Tendons / Q000473:pathology*; D013718:Tensile Strength; D016474:Weight-Bearing
D010455:Peptides; D003094:Collagen