Mayuram Ravikumar, Krishnakumar (2008-08). Region-specific role of water in collagen unwinding and assembly. Master's Thesis. Thesis uri icon

abstract

  • Conformational stability of the collagen triple helix affects its turnover and determines tissue homeostasis. Although it is known that the presence of imino acids (prolines or hydroxyprolines) confer stability to the molecule, little is known regarding the stability of the imino-poor region lacking imino acids, which plays a key role in collagen cleavage. In particular, there have been continuing debates about the role of water in collagen stability. We addressed these issues using molecular dynamics simulations on 30-residue long collagen triple helices, including a structure that has a biologically relevant 9-residue imino-poor region from type III collagen (Protein Data Bank ID: 1BKV). We characterized the conformational motion of the molecule that differs between imino-rich and imino-poor regions using a torsional map approach. At temperatures of 300 K and above, unwinding initiates at a common cleavage site, the glycine-isoleucine bond in the imino-poor region. This provides a linkage between previous observations that unwinding of the imino-poor region is a requirement for collagenase cleavage, and that isolated collagen molecules are unstable at body temperature. Unwinding of the imino-poor region is controlled by dynamic water bridges between backbone atoms with average lifetimes on the order of a few picoseconds, as the degree of unwinding strongly correlated with the loss of water bridges, and unwinding could be either prevented or enhanced, respectively by enforcing or forbidding water bridge formation. While individual water bridges were short-lived in the imino-poor region, the hydration shell surrounding the entire molecule was stable even at 330 K. The diameter of the hydrated collagen including the first hydration shell was about 14 ?, in good agreement with the experimentally measured inter-collagen distances. These results elucidate the general role of water in collagen turnover: water not only affects collagen cleavage by controlling its torsional motion, but it also forms a larger-scale lubrication layer mediating collagen self-assembly.
  • Conformational stability of the collagen triple helix affects its turnover and

    determines tissue homeostasis. Although it is known that the presence of imino

    acids (prolines or hydroxyprolines) confer stability to the molecule, little is known

    regarding the stability of the imino-poor region lacking imino acids, which plays a

    key role in collagen cleavage. In particular, there have been continuing debates about

    the role of water in collagen stability. We addressed these issues using molecular

    dynamics simulations on 30-residue long collagen triple helices, including a structure

    that has a biologically relevant 9-residue imino-poor region from type III collagen

    (Protein Data Bank ID: 1BKV). We characterized the conformational motion of the

    molecule that differs between imino-rich and imino-poor regions using a torsional map

    approach. At temperatures of 300 K and above, unwinding initiates at a common

    cleavage site, the glycine-isoleucine bond in the imino-poor region. This provides

    a linkage between previous observations that unwinding of the imino-poor region

    is a requirement for collagenase cleavage, and that isolated collagen molecules are

    unstable at body temperature. Unwinding of the imino-poor region is controlled by

    dynamic water bridges between backbone atoms with average lifetimes on the order

    of a few picoseconds, as the degree of unwinding strongly correlated with the loss

    of water bridges, and unwinding could be either prevented or enhanced, respectively

    by enforcing or forbidding water bridge formation. While individual water bridges

    were short-lived in the imino-poor region, the hydration shell surrounding the entire

    molecule was stable even at 330 K. The diameter of the hydrated collagen including the first hydration shell was about 14 ?, in good agreement with the experimentally

    measured inter-collagen distances. These results elucidate the general role of water in

    collagen turnover: water not only affects collagen cleavage by controlling its torsional

    motion, but it also forms a larger-scale lubrication layer mediating collagen self-assembly.

publication date

  • August 2008