Protein aggregation rate depends on mechanical stability of fibrillar structure.

The formation of the fibrillar structure of amyloid proteins/peptides is believed to be associated with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Since the rate of aggregation can influence neurotoxicity, finding the key factors that control this rate is of paramount importance. It was recently found that the rate of protein aggregation is related to the mechanical stability of the fibrillar structure such that the higher the mechanical stability, the faster the fibril is formed. However, this conclusion was supported by a limited dataset. In this work, we expand the previous study to a larger dataset, including the wild type of Aß42 peptide and its 20 mutants, the aggregation rate of which was measured experimentally. By using all-atom steered molecular dynamics (SMD) simulations, we can assess the mechanical stability of the fibril structure, which is characterized by the rupture force, pulling work, and unbinding free energy barrier. Our result confirms that mechanical stability is indeed related to the aggregation rate. Since the estimation of the aggregation rate using all-atom simulations is almost forbidden by the current computational capabilities, our result is useful for predicting it based on information obtained from fast SMD simulations for fibrils.

Molecular Insight into the Self-Assembly Process of Cellulose Iß Microfibril.

The self-assembly process of ß-D-glucose oligomers on the surface of cellulose Iß microfibril involves crystallization, and this process is analyzed herein, in terms of the length and flexibility of the oligomer chain, by means of molecular dynamics (MD) simulations. The characterization of this process involves the structural relaxation of the oligomer, the recognition of the cellulose I microfibril, and the formation of several hydrogen bonds (HBs). This process is monitored on the basis of the changes in non-bonded energies and the interaction with hydrophilic and hydrophobic crystal faces. The oligomer length is considered a parameter for capturing insight into the energy landscape and its stability in the bound form with the cellulose I microfibril. We notice that the oligomer-microfibril complexes are more stable by increasing the number of hydrogen bond interactions, which is consistent with a gain in electrostatic energy. Our studies highlight the interaction with hydrophilic crystal planes on the microfibril and the acceptor role of the flexible oligomers in HB formation. In addition, we study by MD simulation the interaction between a protofibril and the cellulose I microfibril in solution. In this case, the main interaction consists of the formation of hydrogen bonds between hydrophilic faces, and those HBs involve donor groups in the protofibril.

Aggregation rate of amyloid beta peptide is controlled by beta-content in monomeric state.

Understanding the key factors that govern the rate of protein aggregation is of immense interest since protein aggregation is associated with a number of neurodegenerative diseases. Previous experimental and theoretical studies have revealed that the hydrophobicity, charge, and population of the fibril-prone monomeric state control the fibril formation rate. Because the fibril structures consist of cross beta sheets, it is widely believed that those sequences that have a high beta content (ß) in the monomeric state should have high aggregation rates as the monomer can serve as a template for fibril growth. However, this important fact has never been explicitly proven, motivating us to carry out this study. Using replica exchange molecular dynamics simulation with implicit water, we have computed ß of 19 mutations of amyloid beta peptide of 42 residues (Aß42) for which the aggregation rate κ has been measured experimentally. We have found that κ depends on ß in such a way that the higher the propensity to aggregation, the higher the beta content in the monomeric state. Thus, we have solved a long-standing problem of the dependence of fibril formation time of the ß-structure on a quantitative level.

Nanomechanical Stability of Aß Tetramers and Fibril-like Structures: Molecular Dynamics Simulations.

Alzheimer's disease (AD) is a neurodegenerative disorder and one of the main causes of dementia. The disease is associated with amyloid beta (Aß) peptide aggregation forming initial clusters and then fibril structure and plaques. Other neurodegenerative diseases such as type 2 diabetes, amyotrophic lateral sclerosis, and Parkinson's disease follow a similar mechanism. Therefore, inhibition of Aß aggregation is considered an effective way to prevent AD. Recent experiments have provided evidence that oligomers are more toxic agents than mature fibrils, prompting researchers to investigate various factors that may influence their properties. One of these factors is nanomechanical stability, which plays an important role in the self-assembly of Aß and possibly other proteins. This stability is also likely to be related to cell toxicity. In this work, we compare the mechanical stability of Aß-tetramers and fibrillar structures using a structure-based coarse-grained (CG) approach and all-atom molecular dynamics simulation. Our results support the evidence for an increase in mechanical stability during the Aß fibrillization process, which is consistent with in vitro AFM characterization of Aß42 oligomers. Namely, using a CG model, we showed that the Young modulus of tetramers is lower than that of fibrils and, as follows from the experiment, is about 1 GPa. Hydrogen bonds are the dominant contribution to the detachment of one chain from the Aß fibril fragment. They tend to be more organized along the pulling direction, whereas in the Aß tetramers no preference is observed.