Spontaneous inter-conversion of insulin fibril chirality.
Ontology highlight
ABSTRACT:
SUBMITTER: Kurouski D
PROVIDER: S-EPMC3655902 | biostudies-literature | 2012 Mar
REPOSITORIES: biostudies-literature
Publications
Spontaneous inter-conversion of insulin fibril chirality.
Kurouski Dmitry D Dukor Rina K RK Lu Xuefang X Nafie Laurence A LA Lednev Igor K IK
Chemical communications (Cambridge, England) 20120112 23
Amyloid fibrils are associated with many neurodegenerative diseases and are considered to be the energetically most favorable form of proteins. Here we report that a small pH change initiates spontaneous transformation of insulin fibrils from one polymorph to another. As a result, fibril supramolecular chirality overturns both accompanying morphological and structural changes. ...[more]
Similar Datasets
Project description:The absolute configuration dictates the biological role of chiral molecules in the living world. This is best exemplified by all ribosomally synthesized polypeptides having chiral amino acids only in the l-configuration. However, d-amino acids are also associated with various vital biological processes such as peptidoglycan of the bacterial cell wall, ligands for neurotransmitters, molecules involved in signaling, and precursors of metabolites, to name a few. The occurrence of both l- and d-enantiomers of amino acids in the living systems necessitates the presence of enzymes that exhibit stereoselectivity in recognition of substrates. This mini-review summarizes the overall mechanistic insights into the interconversion of l- and d-amino acids by the amino acid racemases. We discuss the structural, mechanistic, and evolutionary relationship of four crucial enzymes that catalyze the oxidative deamination of l- or d-amino acids and their physiological role in microbes and higher organisms. We highlight the physiological implications of d-amino acid oxidase and d-aspartate oxidase in human health and diseases and their applications as drug targets. Finally, we summarize the potential applications of microbially obtained chiral-selective enzymes as biocatalysts and for various industrial purposes.
| S-EPMC10851380 | biostudies-literature
Project description:Coalescence of [60]fullerenes potentially produces hypothetical nanocarbon assemblies with non-naturally occurring topologies. Since the discovery of [60]fullerene in 1985, coalesced [60]fullerene oligomers have only been observed as transient species by transmission electron microscopy during an oligomerization process under a high electron acceleration voltage. Herein, we showcase the rational synthesis of covalent assemblies consisting of inherently chiral open-[60]fullerenes. The crystallographic analyses unveiled double-caged structures of non-conjugated and conjugated inter-[60]fullerene hybrids, in which the two [60]fullerene cages are bounds to each other through a covalent linkage. The former one further assembles via a heterochiral recognition so that four carbon cages are arranged in a tetrahedral manner both in solution and solid state. Reflecting radially-conjugated double π-surface nature, the inter-[60]fullerene conjugate exhibits strong electronic communication in its reduced states, intense absorption behavior, and chiroptical activity with a dissymmetry factor of 0.21 (at 674 nm) which breaks the record for known chiral organic molecules.
| S-EPMC10789730 | biostudies-literature
Project description:Fibrils are ?-sheet-rich aggregates that are generally composed of several protofibrils and may adopt variable morphologies, such as twisted ribbons or flat-like sheets. This polymorphism is observed for many different amyloid associated proteins and polypeptides. In a previous study we proposed the existence of another level of amyloid polymorphism, namely, that associated with fibril supramolecular chirality. Two chiral polymorphs of insulin, which can be controllably grown by means of small pH variations, exhibit opposite signs of vibrational circular dichroism (VCD) spectra. Herein, using atomic force microscopy (AFM) and scanning electron microscopy (SEM), we demonstrate that indeed VCD supramolecular chirality is correlated not only by the apparent fibril handedness but also by the sense of supramolecular chirality from a deeper level of chiral organization at the protofilament level of fibril structure. Our microscopic examination indicates that normal VCD fibrils have a left-handed twist, whereas reversed VCD fibrils are flat-like aggregates with no obvious helical twist as imaged by atomic force microscopy or scanning electron microscopy. A scheme is proposed consistent with observed data that features a dynamic equilibrium controlled by pH at the protofilament level between left- and right-twist fibril structures with distinctly different aggregation pathways for left- and right-twisted protofilaments.
| S-EPMC3414895 | biostudies-other
Project description:In the rare medical condition termed injection amyloidosis, extracellular fibrils of insulin are observed. We found that the segment of the insulin B-chain with sequence LVEALYL is the smallest segment that both nucleates and inhibits the fibrillation of full-length insulin in a molar ratio-dependent manner, suggesting that this segment is central to the cross-beta spine of the insulin fibril. In isolation from the rest of the protein, LVEALYL forms microcrystalline aggregates with fibrillar morphology, the structure of which we determined to 1 A resolution. The LVEALYL segments are stacked into pairs of tightly interdigitated beta-sheets, each pair displaying the dry steric zipper interface typical of amyloid-like fibrils. This structure leads to a model for fibrils of human insulin consistent with electron microscopic, x-ray fiber diffraction, and biochemical studies.
| S-EPMC2776439 | biostudies-literature
Project description:Our understanding of the left-right (LR) asymmetry of embryonic development, in particular the contribution of intrinsic handedness of the cell or cell chirality, is limited due to the confounding systematic and environmental factors during morphogenesis and a ack of physiologically relevant in vitro 3D platforms. Here we report an efficient two-layered biomaterial platform for determining the chirality of individual cells, cell aggregates, and self-organized hollow epithelial spheroids. This bioengineered niche provides a uniform defined axis allowing for cells to rotate spontaneously with a directional bias toward either clockwise or counterclockwise directions. Mechanistic studies reveal an actin-dependent, cell-intrinsic property of 3D chirality that can be mediated by actin cross-linking via α-actinin-1. Our findings suggest that the gradient of extracellular matrix is an important biophysicochemical cue influencing cell polarity and chirality. Engineered biomaterial systems can serve as an effective platform for studying developmental asymmetry and screening for environmental factors causing birth defects.
| S-EPMC6275504 | biostudies-literature
Project description:Nanocellulose fibrils are ubiquitous in nature and nanotechnologies but their mesoscopic structural assembly is not yet fully understood. Here we study the structural features of rod-like cellulose nanoparticles on a single particle level, by applying statistical polymer physics concepts on electron and atomic force microscopy images, and we assess their physical properties via quantitative nanomechanical mapping. We show evidence of right-handed chirality, observed on both bundles and on single fibrils. Statistical analysis of contours from microscopy images shows a non-Gaussian kink angle distribution. This is inconsistent with a structure consisting of alternating amorphous and crystalline domains along the contour and supports process-induced kink formation. The intrinsic mechanical properties of nanocellulose are extracted from nanoindentation and persistence length method for transversal and longitudinal directions, respectively. The structural analysis is pushed to the level of single cellulose polymer chains, and their smallest associated unit with a proposed 2 × 2 chain-packing arrangement.
| S-EPMC4491835 | biostudies-other
Project description:Crystals that show mechanical response against various stimuli are of great interest. These stimuli induce polymorphic transitions, isomerizations, or chemical reactions in the crystal and the strain generated between the daughter and parent domains is transcribed into mechanical response. We observed that the crystals of modified dipeptide LL (N3-l-Ala-l-Val-NHCH2C?CH) undergo spontaneous twisting to form right-handed twisted crystals not only at room temperature but also at 0 °C over time. Using various spectroscopic techniques, we have established that the twisting is due to the spontaneous topochemical azide-alkyne cycloaddition (TAAC) reaction at room temperature or lower temperatures. The rate of twisting can be increased by heating, exploiting the faster kinetics of the TAAC reaction at higher temperatures. To address the role of molecular chirality in the direction of twisting the enantiomer of dipeptide LL, N3-d-Ala-d-Val-NHCH2C?CH (DD), was synthesized and topochemical reactivity and mechanoresponse of its crystals were studied. We have found that dipeptide DD not only underwent TAAC reaction, giving 1,4-triazole-linked pseudopolypeptides of d-amino acids, but also underwent twisting with opposite handedness (left-handed twisting), establishing the role of molecular chirality in controlling the direction of mechanoresponse. This paper reports (i) a mechanical response due to a thermal reaction and (ii) a spontaneous mechanical response in crystals and (iii) explains the role of molecular chirality in the handedness of the macroscopic mechanical response.
| S-EPMC5866578 | biostudies-literature
Project description:One of the most well-recognized stereogenic elements in a chiral molecule is an sp(3)-hybridized carbon atom that is connected to four different substituents. Axes of chirality can also exist about bonds with hindered barriers of rotation; molecules containing such axes are known as atropisomers. Understanding the dynamics of these systems can be useful, for example, in the design of single-atropisomer drugs or molecular switches and motors. For molecules that exhibit a single axis of chirality, rotation about that axis leads to racemization as the system reaches equilibrium. Here we report a two-axis system for which an enantioselective reaction produces four stereoisomers (two enantiomeric pairs): following a catalytic asymmetric transformation, we observe a kinetically controlled product distribution that is perturbed from the system's equilibrium position. As the system undergoes isomerization, one of the diastereomeric pairs drifts spontaneously to a higher enantiomeric ratio. In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases. These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes--one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides. The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium.
| S-EPMC4008667 | biostudies-literature
Project description:Long-chain unsaturated and polyunsaturated fatty acids (LCUFAs and LCPUFAs, respectively) are the essential components of phospholipids and sphingolipids, major building blocks of plasma and organelle membranes. These molecules are also involved in cell signaling and energy metabolism. Hence, both LCUFAs and LCPUFAs are broadly used as food supplements. However, the role of these fatty acids (FAs) in the self-assembly of misfolded proteins remains unclear. In this study, we investigated the effect of LCUFAs and LCPUFAs, as well as their saturated analogue, on insulin aggregation. Using vibrational circular dichroism, we found that all analyzed FAs reversed the supramolecular chirality of insulin fibrils. Molecular dynamics simulations showed that strong hydrophobic interactions were formed between the long aliphatic tails of FAs and hydrophobic amino acid residues of insulin. We infer that such insulin:FA complexes had different self-assembly mechanisms compared to that of insulin alone, which resulted in the observed reversal of the supramolecular chirality of the amyloid fibrils.
| S-EPMC10863027 | biostudies-literature
Project description:Assembly of normally soluble proteins into amyloid fibrils is a cause or associated symptom of numerous human disorders, including Alzheimer's and the prion diseases. We report molecular-level simulation of spontaneous fibril formation. Systems containing 12-96 model polyalanine peptides form fibrils at temperatures greater than a critical temperature that decreases with peptide concentration and exceeds the peptide's folding temperature, consistent with experimental findings. Formation of small amorphous aggregates precedes ordered nucleus formation and subsequent rapid fibril growth through addition of beta-sheets laterally and monomeric peptides at fibril ends. The fibril's structure is similar to that observed experimentally.
| S-EPMC526199 | biostudies-literature