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Collagen is the most abundant protein in mammals. In many tissues, collagen molecules assemble to form a hierarchical structure. In the smallest supramolecular unit, named fibril, each molecule is displaced in the axial direction with respect to its neighbors. This staggering creates a periodic gap and overlap regions, where the gap regions exhibit 20% less density. These fibril-forming collagens play an essential role in the strength of connective tissues. Despite much effort, directed at understanding collagen function and regulation, the influence of the chemical environment on the local structural and mechanical properties remains poorly understood. Recent studies, aimed at elucidating the effect of osmotic pressure, showed that collagen contracts upon water removal. This observation highlights the importance of water for the stabilization and mechanics of the collagen molecule.
Using collagen mimetic peptides (CMPs), which fold into triple helical structures reminiscent of natural collagen, the primary goal of this work was to investigate the effect of the osmotic pressure on specific collagen-mimetic sequences. CMPs were used as the model system as they provide sequence control, which is essential for discriminating local from global structural changes and for relating the observed effects to existing knowledge about the full-length collagen molecule. Of specific interest was the structure of individual collagen triple helices as well as their organization into self-assembled higher order structures. These key structural features were monitored with infrared spectroscopy (IR) and synchrotron X-ray scattering, while varying the osmotic pressure. For controlling the osmotic pressure, CMP powder samples were incubated in air of defined relative humidity, ranging from dry conditions to highly “humid”. In addition, to obtain more biologically relevant conditions, the CMPs were measured in ultrapure water and in solutions containing small molecule osmolytes.
Using the sequences (Pro-Pro-Gly)10, (Pro-Hyp-Gly)10 and (Hyp-Hyp-Gly)10, it was shown that CMPs with different degrees of proline hydroxylation (Hyp = hydroxyproline) exhibit a sequence-specific response to osmotic pressure. IR spectroscopy revealed that osmotic pressure changes affect the strength of the triple helix stabilizing, interchain hydrogen bond and that the extent of this change depends on the degree of hydroxylation. X-ray scattering experiments further showed that changes in osmotic pressure affect both the molecular length as well as the higher order organization of CMPs. Starting from a pseudo-hexagonal packing in the dry state, all three CMPs showed isotropic swelling when increasing the water content to approximately 1.2 water molecules per amino acid, again to different extents depending on the degree of hydroxylation. When increasing the water content further, this pseudo-hexagonal arrangement breaks down. In the fully hydrated state, each CMP is characterized by its own specific and more complex packing geometry.
While these changes in the lateral packing arrangement suggest swelling upon hydration, an overall decrease of the molecular length (i.e. contraction) was observed in the axial direction. Also for this structural feature, a strong dependency on the specific amino acid sequence was found. Interestingly, the observed contraction is the opposite of what has been reported for natural collagen. As (Pro-Pro-Gly)n, (Pro-Hyp-Gly)n and (Hyp-Hyp-Gly)n repeat units are found in collagen with a relatively high abundance, this suggests that other collagen sequence fragments need to respond to hydration in the opposite way to obtain a net elongation of the full-length collagen molecule.
To test this hypothesis, sequences predicted to be sensitive to osmotic pressure were considered. One such sequence, consisting of two repeat units (Ala-Arg-Gly-Ser-Asp-Gly), was inserted as a guest into a (Pro-Pro-Gly) host. When compared to the canonical CMP sequences investigated earlier, the lateral helix packing follows a similar trend with increasing hydration; however, the host-guest CMP axially elongates with increasing water content. This behavior is more similar to what has been found for natural collagen and suggests that different sequences do determine the molecular length of collagen sequences differently. Interestingly, the canonical sequences are more abundant in the overlap region while the guest sequence is found in the gap region. This allows to speculate that sequences in the gap and overlap regions possess a specifically fine-tuned local response to osmotic pressure changes. Clearly, more experiments with additional sequences are needed to confirm this.
In conclusion, the results obtained in this work indicate a highly sequence specific interaction between collagen and water. Osmotic pressure-induced conformational changes mostly originate from local geometries and bonding patterns and affect both the structure of individual triple helices as well as higher order assemblies. One key remaining question is how these conformational changes affect the local mechanical properties of the collagen molecule. As a first step, the stiffness (persistence length) of full-length collagen was determined using atomic force microscopy. In the future, experimental strategies need to be developed that allow for investigating the mechanical properties of specific collagen sequences, e.g. performing single-molecule force spectroscopy of CMPs.
Being ignorant of key aspects of a strategic interaction can represent an advantage rather than a handicap. We study one particular context in which ignorance can be beneficial: iterated strategic interactions in which voluntary cooperation may be sustained into the final round if players voluntarily forego knowledge about the time horizon. We experimentally examine this option to remain ignorant about the time horizon in a finitely repeated two-person prisoners’ dilemma game. We confirm that pairs without horizon knowledge avoid the drop in cooperation that otherwise occurs toward the end of the game. However, this effect is superposed by cooperation declining more rapidly in pairs without horizon knowledge during the middle phase of the game, especially if players do not know that the other player also wanted to remain ignorant of the time horizon.
Sinkholes and depressions are typical landforms of karst regions. They pose a considerable natural hazard to infrastructure, agriculture, economy and human life in affected areas worldwide. The physio-chemical processes of sinkholes and depression formation are manifold, ranging from dissolution and material erosion in the subsurface to mechanical subsidence/failure of the overburden. This thesis addresses the mechanisms leading to the development of sinkholes and depressions by using complementary methods: remote sensing, distinct element modelling and near-surface geophysics.
In the first part, detailed information about the (hydro)-geological background, ground structures, morphologies and spatio-temporal development of sinkholes and depressions at a very active karst area at the Dead Sea are derived from satellite image analysis, photogrammetry and geologic field surveys. There, clusters of an increasing number of sinkholes have been developing since the 1980s within large-scale depressions and are distributed over different kinds of surface materials: clayey mud, sandy-gravel alluvium and lacustrine evaporites (salt). The morphology of sinkholes differs depending in which material they form: Sinkholes in sandy-gravel alluvium and salt are generally deeper and narrower than sinkholes in the interbedded evaporite and mud deposits. From repeated aerial surveys, collapse precursory features like small-scale subsidence, individual holes and cracks are identified in all materials. The analysis sheds light on the ongoing hazardous subsidence process, which is driven by the base-level fall of the Dead Sea and by the dynamic formation of subsurface water channels.
In the second part of this thesis, a novel, 2D distinct element geomechanical modelling approach with the software PFC2D-V5 to simulating individual and multiple cavity growth and sinkhole and large-scale depression development is presented. The approach involves a stepwise material removal technique in void spaces of arbitrarily shaped geometries and is benchmarked by analytical and boundary element method solutions for circular cavities. Simulated compression and tension tests are used to calibrate model parameters with bulk rock properties for the materials of the field site. The simulations show that cavity and sinkhole evolution is controlled by material strength of both overburden and cavity host material, the depth and relative speed of the cavity growth and the developed stress pattern in the subsurface. Major findings are: (1) A progressively deepening differential subrosion with variable growth speed yields a more fragmented stress pattern with stress interaction between the cavities. It favours multiple sinkhole collapses and nesting within large-scale depressions. (2) Low-strength materials do not support large cavities in the material removal zone, and subsidence is mainly characterised by gradual sagging into the material removal zone with synclinal bending. (3) High-strength materials support large cavity formation, leading to sinkhole formation by sudden collapse of the overburden. (4) Large-scale depression formation happens either by coalescence of collapsing holes, block-wise brittle failure, or gradual sagging and lateral widening.
The distinct element based approach is compared to results from remote sensing and geophysics at the field site. The numerical simulation outcomes are generally in good agreement with derived morphometrics, documented surface and subsurface structures as well as seismic velocities. Complementary findings on the subrosion process are provided from electric and seismic measurements in the area.
Based on the novel combination of methods in this thesis, a generic model of karst landform evolution with focus on sinkhole and depression formation is developed. A deepening subrosion system related to preferential flow paths evolves and creates void spaces and subsurface conduits. This subsequently leads to hazardous subsidence, and the formation of sinkholes within large-scale depressions. Finally, a monitoring system for shallow natural hazard phenomena consisting of geodetic and geophysical observations is proposed for similarly affected areas.
On doubling unconditionals
(2019)
A form-function mismatch?
(2019)