ColBuilder: A server to build collagen fibril models

Abstract

Type I collagen is the main structural component of many tissues in the human body. It provides excellent mechanical properties to connective tissue and acts as a protein interaction hub. There is thus a wide interest in understanding the properties and diverse functions of type I collagen at the molecular level. A precondition is an atomistic collagen I structure as it occurs in native tissue. To this end, we built full-atom models of cross-linked collagen fibrils by integrating the low-resolution structure of collagen fibril available from x-ray fiber diffraction with high-resolution structures of short collagen-like peptides from x-ray crystallography and mass spectrometry data. We created a Web resource of collagen models for 20 different species with a large variety of cross-link types and localization within the fibril to facilitate structure-based analyses and simulations of type I collagen in health and disease. To easily enable simulations, we provide parameters of the modeled cross-links for an Amber force field. The repository of collagen models is available at https://colbuilder.h-its.org.

Figure 1

Types of enzymatic collagen cross-links. Divalent cross-links are formed between two side chains, one of the telopeptide region and the other one of the triple helical regions of the neighboring collagen molecule. Trivalent cross-links are formed between two residues of the telopeptide region of one collagen molecule and one of the triple helical regions of the neighboring collagen molecule. To see this figure in color, go online.

Figure 2

Positioning of cross-links. Examples are shown for cross-links between the N-telopeptide (bottom) and an adjacent triple helix (top). Chains and the cross-linked residues of these chains are color-coded (green, red: α1, yellow: α2). For a complete list of possible cross-link positions, see Figs. S3 and S4. To see this figure in color, go online.

Figure 3

Example model of a type I collagen fibril available through the ColBuilder Web resource. The model corresponds to a representative unit of a human collagen fibril with eight pyridinoline (PYD) N-terminal cross-links and eight hydroxylysino-keto-norleucine (HLKNL) C-terminal cross-links. It comprises 41 triple helices spanning one central overlap and one gap region (in two parts, left and right). Triple helices are colored according to the staggering distance; cross-links are shown in blue or colored by atom type. To see this figure in color, go online.

Figure 4

Comparison to experimental data. (a) Overlap/gap ratio as given by the length of overlap region (measured as shown in the upper figure) and overall D-period length is at most, taking full telopeptide region into account, 0.485/0.515. (b) Distribution of Tyr (blue) and His (red) along fiber model as observed in our model and 3HR2 with different telopeptide conformation is shown and compared with regions, in which iodination (marking Tyr and His) is above the noise (boxed areas, Orgel et al. (12)). (c) Gap and overlap lengths for the complete set of our 12 simulations: starting from a configuration as shown in (a), the overlap distances and, hence, the average ratio decreases to ~0.465/0.535 (bold line: average, transparent lines: individual replica) (d) All-to-all distances between the center of masses of the triple helix (a cross-sectional slice of the overlap region thereof) at 0, 50, and 100 ns simulation time. The counts in the histograms are summed up across all our models, whereas an exemplary slice for one individual replica (R. norvegicus, HLKNL cross-link) is shown on the right. The dashed lines in the histogram indicate the average distance to nearest, next, and over-next nearest neighbors. To see this figure in color, go online.