While amyloid formation has been implicated in the pathology of over twenty human diseases, the rational design of amyloid inhibitors is hampered by a lack of structural information about amyloid-inhibitor complexes. We use isotope labeling and two-dimensional infrared spectroscopy to obtain a residue-specific structure for the complex of human amylin, the peptide responsible for islet amyloid formation in type 2 diabetes, with a known inhibitor, rat amylin. Based on its sequence, rat amylin should block formation of the C-terminal β-sheet, but at 8 hours after mixing rat amylin blocks the N-terminal β-sheet instead. At 24 hours after mixing, rat amylin blocks neither β-sheet and forms its own β-sheet most likely on the outside of the human fibrils. This is striking because rat amylin is natively disordered and not previously known to form amyloid β-sheets. The results show that even seemingly intuitive inhibitors may function by unforeseen and complex structural processes.
Glasses are generally prepared by cooling from the liquid phase, and their properties depend on their thermal history. Recent experiments indicate that glasses prepared by vapour deposition onto a substrate can exhibit remarkable stability, and might correspond to equilibrium states that could hitherto be reached only by glasses aged for thousands of years. Here we create ultrastable glasses by means of a computer-simulation process that mimics physical vapour deposition. These stable glasses have, far below the conventional glass-transition temperature, the properties expected for the equilibrium supercooled liquid state, and optimal stability is attained when deposition occurs at the Kauzmann temperature. We also show that the glasses' extraordinary stability is associated with distinct structural motifs, in particular the abundance of regular Voronoi polyhedra and the relative lack of irregular polyhedra.
Patients with type II diabetes exhibit fibrillar deposits of human amylin protein in the pancreas. It has been proposed that amylin oligomers arising along the aggregation or fibril-formation pathways are important in the genesis of the disease. In a step toward understanding these aggregation pathways, in this work we report the conformational preferences of human amylin monomer in solution using molecular simulations and infrared experiments. In particular, we identify a stable conformer that could play a key role in aggregation. We find that amylin adopts three stable conformations: one with an α-helical segment comprising residues 9-17 and a short antiparallel β-sheet comprising residues 24-28 and 31-35; one with an extended antiparallel β-hairpin with the turn region comprising residues 20-23; and one with no particular structure. Using detailed calculations, we determine the relative stability of these various conformations, finding that the β-hairpin conformation is the most stable, followed by the α-helical conformation, and then the unstructured coil. To test our predicted structure, we calculate its infrared spectrum in the amide I stretch regime, which is sensitive to secondary structure through vibrational couplings and linewidths, and compare it to experiment. We find that theoretically predicted spectra are in good agreement with the experimental line shapes presented herein. The implications of the monomer secondary structures on its aggregation pathway and on its interaction with cell membranes are discussed.
The aggregation of human amylin to form amyloid contributes to islet β-cell dysfunction in type 2 diabetes. Studies of amyloid formation have been hindered by the low structural resolution or relatively modest time resolution of standard methods. Two-dimensional infrared (2DIR) spectroscopy, with its sensitivity to protein secondary structures and its intrinsic fast time resolution, is capable of capturing structural changes during the aggregation process. Moreover, isotope labeling enables the measurement of residue-specific information. The diagonal line widths of 2DIR spectra contain information about dynamics and structural heterogeneity of the system. We illustrate the power of a combined atomistic molecular dynamics simulations and theoretical and experimental 2DIR approach by analyzing the variation in diagonal line widths of individual amide I modes in a series of labeled samples of amylin amyloid fibrils. The theoretical and experimental 2DIR line widths suggest a “W” pattern, as a function of residue number. We show that large line widths result from substantial structural disorder, and that this pattern is indicative of the stable secondary structure of the two β-sheet regions. This work provides a protocol for bridging MD simulation and 2DIR experiments for future aggregation studies.
Recently, novel organic glassy materials that exhibit remarkable stability have been prepared by vapor deposition. The thermophysical properties of these new "stable" glasses are equivalent to those that common glasses would exhibit after aging over periods lasting thousands of years. The origin of such enhanced stability has been elusive; in the absence of detailed models, past studies have discussed the formation of new polyamorphs or that of nanocrystals to explain the observed behavior. In this work, an atomistic molecular model of trehalose, a disaccharide of glucose, is used to examine the properties of vapor-deposited stable glasses. Consistent with experiment, the model predicts the formation of stable glasses having a higher density, a lower enthalpy, and higher onset temperatures than those of the corresponding "ordinary" glass formed by quenching the bulk liquid. Simulations reveal that newly formed layers of the growing vapor-deposited film exhibit greater mobility than the remainder of the material, thereby enabling a reorganization of the film as it is grown. They also reveal that "stable" glasses exhibit a distinct layered structure in the direction normal to the substrate that is responsible for their unusual properties.
The formation of human islet amyloid polypeptide (hIAPP) is implicated in the loss of pancreatic β-cells in type II diabetes. Rat amylin, which differs from human amylin at six residues, does not lead to formation of amyloid fibrils. Pramlintide is a synthetic analog of human amylin that shares three proline substitutions with rat amylin. Pramlintide has a much smaller propensity to form amyloid aggregates and has been widely prescribed in amylin replacement treatment. It is known that the three prolines attenuate β-sheet formation. However, the detailed effects of these proline substitutions on full-length hIAPP remain poorly understood. In this work, we use molecular simulations and bias-exchange metadynamics to investigate the effect of proline substitutions on the conformation of the hIAPP monomer. Our results demonstrate that hIAPP can adopt various β-sheet conformations, some of which have been reported in experiments. The proline substitutions perturb the formation of long β-sheets and reduce their stability. More importantly, we find that all three proline substitutions of pramlintide are required to inhibit β conformations and stabilize the α-helical conformation. Fewer substitutions do not have a significant inhibiting effect.
The possible exotic cluster decay modes of some "stable" nuclei in the region 50 & Z & 82 are calculated using a preformed cluster model. The predicted half-life times for certain cluster decays of &6 Ba« and 80 Hg&06 nuclei, which lie in the neighborhood of the spherical magic shells Z =50 and 82 and the deformed magic shell N = 108, are interesting cases of possible instabilities present in regions of "stable" nuclei. These are the ' C and ' 0 decays of ' Ba and the Be decay of ' Hg, whose half-life times are predicted to be -10, 10,and 10 s, respectively. The last case is an exciting new possibility of cluster radioactivity with a deformed daughter nucleus. Experimentally, however, both parent nuclei are short lived and their suggested cluster decays cannot be observed. In any case, the present study invokes further work to look for other similar instabilities in various regions of "stable" nuclei. It is possible that some of these decays are measurable and can be used to obtain the related new nuclear structure effects.The effects of reinforcement of shell gaps for nuclei with weak spherical closed shell at Z =64 and deformation starting to begin at N-90 are also discussed.PACS number(s): 23.60.+e, 23.90.+ w, 21.90.+f, 27.70.+q
This paper is a sequel to a study which showed that the dominant dimension for perceptual discrimination among normal voices was the male-female categorization and which also suggested that discrimination within the male-female categories utilized distinct dimenisons. The present study eliminates the male-female axis by treating the gender groups separately and making the within-category dimensions available for more sensitive analysis. The purpose was to determine the number and nature of perceptual parameters needed to explain judgments of voice similarity depending on talker sex and whether the stimulus sample was a sustained vowel or a short phrase. The similarity judgments were submitted to multidimensional analysis via INDSCAL and the resulting dimenisons were interpreted in terms of available acoustic measures and unidimensional voice-quality ratings of pitch, breathiness, hoarseness, nasality, and effort. The decisions of the listerners appeared to be influenced by both the sex of the speaker and the stimulus sample, although fundamental frequency (fo), was important for all judgments. Aside from the fo dimensions, judgments concerning male voices were related to vocal tract parameters, while similarity judgments of female voices were related to perceived glottal/vocal tranct differences. Formant structure was apparently important in judging the similarity of vowels for both sexes while perceptual glottal/temporal attributes may have been used as cues in the judgments of phrases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.