Hydration Profiles of Amyloidogenic Molecular Structures

Abstract

Hydration shells of normal proteins display regions of highly structured water as well as patches of less structured bulk-like water. Recent studies suggest that isomers with larger surface densities of patches of bulk-like water have an increased propensity to aggregate. These aggregates are toxic to the cellular environment. Hence, the early detection of these toxic deposits is of paramount medical importance. We show that various morphological states of association of such isomers can be differentiated from the normal protein background based on the characteristic partition between bulk, caged, and surface hydration water and the magnetic resonance (MR) signals of this water. We derive simple mathematical equations relating the compartmentalization of water to the local hydration fraction and the packing density of the newly formed molecular assemblies. Then, we employ these equations to predict the MR response of water constrained by protein aggregation. Our results indicate that single units and compact aggregates that contain no water between constituents induce a shift of the MR signal from normal protein background to values in the hyperintensity domain (bright spots), corresponding to bulk water. In contrast, large plaques that cage significant amounts of water between constituents are likely to generate MR responses in the hypointensity domain (dark spots), typical for strongly correlated water. The implication of these results is that amyloids can display both dark and bright spots when compared to the normal gray background tissue on MR images. In addition, our findings predict that the bright spots are more likely to correspond to amyloids in their early stage of development. The results help explain the MR contrast patterns of amyloids and suggest a new approach for identifying unusual protein aggregation related to disease.

Amyloid Oligomer Formation Probed by Water Proton Magnetic Resonance Spectroscopy

“…Recently, Nucci et al (24) demonstrated that water proton magnetic resonance spectroscopy can resolve dynamics of water at the surface of proteins. Moreover, the results (24) suggest that water-rearrangement processes in the next hydration layers closely correlate with hydration properties of specific water patches on the protein surface (25), which was also predicted by computer simulations (22,26,27). The work by Nucci et al (24) supports also the idea (21)(22)(23) that the magnetic relaxation of water in the hydration shells of proteins is a valuable tool to probe pathogenic proteins associated with many diseases.…”

“…Water molecules at the interface with amyloidogenic peptides undergo considerable reorganization during the aggregation process (11,12,(21)(22)(23)31,32). As the peptides associate forming oligomers and fibrils, their hydrophobic patches are buried inside the newly formed amyloidogenic assembly.…”

“…As the peptides associate forming oligomers and fibrils, their hydrophobic patches are buried inside the newly formed amyloidogenic assembly. This gradually liberates more water molecules into the bulklike water phase, decreasing the fraction of water molecules in direct contact with the molecular surface (21)(22)(23). Based on the scaled particle theory (33), we can estimate the amount (DV) of surface water released in the bulk after the oligomerization process.…”

“…Thus, oligomerization can alter the bulklike/surface-water ratio and induce rearrangements of local solvent networks in ways that may enable oligomer detection. Previous studies suggested that surface hydration properties of proteins determine the microscopic magnetic relaxation response of surrounding water (21)(22)(23)(24).…”

Optical properties of the lens: an explanation for the zones of discontinuity

“…The latter have the advantage that they can be conducted in vivo (Kasthurirangan et al, 2008) but are limited in that refractive index is calculated from protein concentrations derived from transverse relaxation times of water protons. This has relevance to soluble protein homogenates (Hills et al, 1989) but takes no account of insoluble protein or the fact that water in the intact lens exist in free and bound states and that these produce differences in transverse relaxation times (Despa et al, 2008). These factors are particularly significant for any conclusions about age-related changes in refractive index given that with age there is an increase in both insoluble protein (Pirie, 1968;Satoh, 1972;Lahm et al, 1985) and free water (Lahm et al, 1985;Bettelheim et al, 2002;Heys et al, 2008).…”