Insulin Complexation with Cyclodextrins—A Molecular Modeling Approach

Around 5% of the population of the world is affected with the disease called diabetes mellitus. The main medication of the diabetes is the insulin; the active form is the insulin monomer, which is an instable molecule, because the long storage time, or the high temperature, can cause the monomer insulin to adapt an alternative fold, rich in β-sheets, which is pharmaceutically inactive. The aim of this study is to form different insulin complexes with all the cyclodextrin used for pharmaceutical excipients (native cyclodextrin, methyl, hydroxyethyl, hydroxypropyl and sulfobutylether substituted β-cyclodextrin), in silico condition, with the AutoDock molecular modeling program, to determine the best type of cyclodextrin or cyclodextrin derivate to form a complex with an insulin monomer, to predict the molar ratio, the conformation of the complex, and the intermolecular hydrogen bonds formed between the cyclodextrin and the insulin. From the results calculated by the AutoDock program it can be predicted that insulin can make a stable complex with 5–7 molecules of hydroxypropyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin, and by forming a complex potentially can prevent or delay the amyloid fibrillation of the insulin and increase the stability of the molecule.

Exploring the locking stage of NFGAILS amyloid fibrillation via transition manifold analysis

We demonstrate the application of the transition manifold framework to the late-stage fibrillation process of the NFGAILS peptide, a amyloidogenic fragment of the human islet amyloid polypeptide (hIAPP). This framework formulates machine learning methods for the analysis of multi-scale stochastic systems from short, massively parallel molecular dynamical simulations. We identify key intermediate states and dominant pathways of the process. Furthermore, we identify the optimally timescale-preserving reaction coordinate for the dock-lock process to a fixed pre-formed fibril and show that it exhibits strong correlation with the mean native hydrogen-bond distance. These results pave the way for a comprehensive model reduction and multi-scale analysis of amyloid fibrillation processes. Graphic Abstract

Inhibition of Insulin Amyloid Fibrillation by Salvianolic Acids and Calix[n]arenes: Molecular Docking Insight

In this study, the ability of salvianolic acids A, B, C, F, G and calix[[Formula: see text]]arenes ([Formula: see text], 5, 6 and 8) with different upper rims in the inhibition of insulin amyloid fibril formation was studied using molecular docking. The results were analyzed from a molecular point of view. All of the considering ligands interacted with significant residues of insulin, which had a crucial role in the process of insulin fibrillation. The interactions among the ligands and insulin residues could be done through hydrogen bonding and hydrophobic interactions with good binding affinity. So, these ligands could prevent the formation of the insulin fibril. The good consistency of the docking results of [Formula: see text]-sulfonatocalix[4]arene and [Formula: see text]-sulfonatocalix[6]arene with the experimental results in the previous literature represented the capacity of the current theoretical method to supplement and interpret experimental findings. Also, in this study, salvianolic acids A, C, F and G were suggested as new inhibitors of the insulin amyloid fibril.

Dual effects of presynaptic membrane mimetics on α-synuclein amyloid aggregation

Aggregation of intrinsically disordered α-synuclein (αSN) under various conditions is closely related to synucleinopathies. Although various biological membranes have shown to alter the structure and aggregation propensity of αSN, a thorough understanding of the molecular and mechanical mechanism of amyloidogenesis in membranes remains unanswered. Herein, we examined the structural changes, binding properties, and amyloidogenicity of three variations of αSN mutants under two types of liposomes, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and presynaptic vesicle mimetic (Mimic) membranes. While neutrally charged DOPC membranes elicited marginal changes in the structure and amyloid fibrillation of αSNs, negatively charged Mimic membranes induced dramatic helical folding and biphasic amyloid generation. At low concentration of Mimic membranes, the amyloid fibrillation of αSNs was promoted in a dose-dependent manner. However, further increases in the concentration constrained the fibrillation process. These results suggest the dual effect of Mimic membranes on regulating the amyloidogenesis of αSN, which is rationalized by the amyloidogenic structure of αSN and condensation-dilution of local αSN concentration. Finally, we propose physicochemical properties of αSN and membrane surfaces, and their propensity to drive electrostatic interactions as decisive factors of amyloidogenesis.