Region‐specific role of water in collagen unwinding and assembly

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 (PDB ID: 1BKV). A torsional map approach was used to characterize the conformational motion of the molecule that differ between imino-rich and imino-poor regions. At temperatures 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. We found that 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 A, 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.

Molecular basis for optical clearing of collagenous tissues

“…8 Earlier studies suggest that water bridges stabilize collagen tertiary structures and that hydration shell organizes triple helices for higher order assembly. 8,16,20 Characteristic of chemical agents with significant OCP is the ability to form hydrogen bond bridges, which would disrupt hydration layers and affect hydration forces mediating collagen self-assembly. This molecular viewpoint of chemical agent-collagen interaction suggests that hindering the exchange of chemical agent with bound water would preserve the hydration layer, stabilize high-order collagen structures, and hinder tissue optical clearing.…”

“…13,14 On the other hand, peptide 1BKV has a middle region devoid of Pro and Hyp, which is less stable but functionally important for collagen cleavage. 15,16 Using simulations of these structurally and functionally relevant sequences, it is possible to infer polyol interactions with native collagen. The backbone structure of the GPO peptide was built using the THeBuScr collagen building script.…”

“…The backbone structure of the GPO peptide was built using the THeBuScr collagen building script. 17 Side chain atoms were added to the backbone using the existing amino acid topology files and systematically energy minimized as done previously 16 to get the final structure. Polar hydrogens were added to the peptides using the HBUILD facility in CHARMM.…”

Translational and Rotational Dynamics of Water Molecules in Aligned Collagenous Tissues: Implications for Assessing Collagen Organisation with Magnetic Resonance Imaging

“…Fullerton Again, it is noted that studies which seemingly agree with the notion of ice-like bonds [146,147,175,177] are carried out on fibres or fibrils, while those which disagree were concerned with a sole collagen molecule [64,65,148,181]. The key difference is the possible inclusion of intra-fibrillar water in the former.…”

“…These have included simulations of single collagen molecules [64,65,158,181,212,213], and collagen forming larger fibril structures [214][215][216][217][218]. The focus of these studies has primarily been the biomechanical properties [213,214,218] and stability [64,65] of the formed collagen structures, with only a few studies primarily focused on watercollagen interactions [64,158].Handgraaf and Zerbetto [158] studied the distribution and slow-down of water near a collagen peptide that did not contain any single-water bridges of the type Chapter 2: Background and Theory 79 ( Figure 9). They found that the translational diffusion of water in the first hydration shell (~ 2 Å from the protein surface) was 1.5 times slower than in bulk water.…”