RESUMO
Measuring mechanical forces of cell-cell interactions is important for studying morphogenesis in multicellular organisms. We previously reported an image-based statistical method for inferring effective mechanical potentials of pairwise cell-cell interactions by fitting cell tracking data with a theoretical model. However, whether this method is applicable to tissues with non-cellular components such as cavities remains elusive. Here we evaluated the applicability of the method to cavity-harboring tissues. Using synthetic data generated by simulations, we found that the effect of expanding cavities was added to the pregiven potentials used in the simulations, resulting in the inferred effective potentials having an additional repulsive component derived from the expanding cavities. Interestingly, simulations by using the effective potentials reproduced the cavity-harboring structures. Then, we applied our method to the mouse blastocysts, and found that the inferred effective potentials can reproduce the cavity-harboring structures. Pairwise potentials with additional repulsive components were also detected in two-dimensional cell sheets, by which curved sheets including tubes and cups were simulated. We conclude that our inference method is applicable to tissues harboring cavities and cell sheets, and the resultant effective potentials are useful to simulate the morphologies.
RESUMO
Polyglutamine (polyQ) diseases are devastating neurodegenerative disorders characterized by abnormal expansion of glutamine repeats within specific proteins. The aggregation of polyQ proteins is a critical pathological hallmark of these diseases. Arginine was identified as a promising inhibitory compound because it prevents polyQ-protein monomers from forming intra- and intermolecular ß-sheet structures and hinders polyQ proteins from aggregating to form oligomers. Such an aggregation inhibitory effect was not observed in other amino acids. However, the underlying molecular mechanism of the aggregation inhibition and the factors that differentiate arginine from other amino acids, in terms of the inhibition of the polyQ-protein aggregation, remain poorly understood. Here, we performed replica-permutation molecular dynamics simulations to elucidate the molecular mechanism by which arginine inhibits the formation of the intramolecular ß-sheet structure of a polyQ monomer. We found that the intramolecular ß-sheet structure with more than four ß-bridges of the polyQ monomer with arginine is more unstable than without any ligand and with lysine. We also found that arginine has 1.6-2.1 times more contact with polyQ than lysine. In addition, we revealed that arginine forms more hydrogen bonds with the main chain of the polyQ monomer than lysine. More hydrogen bonds formed between arginine and polyQ inhibit polyQ from forming the long intramolecular ß-sheet structure. It is known that intramolecular ß-sheet structure enhances intermolecular ß-sheet structure between proteins. These effects are thought to be the reason for the inhibition of polyQ aggregation. This study provides insights into the molecular events underlying arginine's inhibition of polyQ-protein aggregation.
Assuntos
Arginina , Simulação de Dinâmica Molecular , Peptídeos , Peptídeos/química , Peptídeos/farmacologia , Arginina/química , Ligação de Hidrogênio , Agregados Proteicos/efeitos dos fármacos , Humanos , Agregação Patológica de Proteínas/metabolismoRESUMO
The cause of Alzheimer's disease is related to aggregates such as oligomers and amyloid fibrils consisting of amyloid-ß (Aß) peptides. Molecular dynamics (MD) simulation studies have been conducted to understand the molecular mechanism of the formation and disruption of Aß aggregates. In this Perspective, the MD simulation studies are classified into four categories, focusing on the target systems: aggregation of Aß peptides in bulk solution, Aß aggregation at the interface, aggregation inhibitor against Aß peptides, and nonequilibrium MD simulation of Aß aggregates. MD simulation studies in these categories are first reviewed. Future perspectives in each category are then presented. Finally, the overall perspective is presented on how MD simulations of Aß aggregates can be utilized for developing Alzheimer's disease treatment.
Assuntos
Doença de Alzheimer , Simulação de Dinâmica Molecular , Humanos , Peptídeos beta-Amiloides/química , Amiloide/química , Fragmentos de Peptídeos/químicaRESUMO
Aggregates of amyloid-ß (Aß) peptides are thought to cause Alzheimer's disease. Polyphenolic compounds are known to inhibit Aß aggregation. We applied replica permutation with solute tempering (RPST) to the system of Aß fragments, Aß(16-22), and polyphenols to elucidate the mechanism of inhibition of Aß aggregation. The RPST molecular dynamics simulations were performed for two polyphenols, myricetin (MYC) and rosmarinic acid (ROA). Two Aß fragments were distant, and the number of residues forming the intermolecular ß-sheet was reduced in the presence of MYC and ROA compared with that in the absence of polyphenols. MYC was found to interact with glutamic acid and phenylalanine of Aß fragments. These interactions induce helix structure formation of Aß fragments, making it difficult to form ß-sheet. ROA interacted with glutamic acid and lysine, which reduced the hydrophilic interaction between Aß fragments. These results indicate that these polyphenols inhibit the aggregation of Aß fragments with different mechanisms.