Volume 5, Issue 9, September 2015
- SPECIAL TOPIC: AMYLOID AGGREGATION: CHARACTERIZATION, FUNCTION AND MOLECULAR MECHANISMS
- Invited Articles from the 10th International Conference for Computational Methods in Science and Engineering (ICCMSE)
5(2015); http://dx.doi.org/10.1063/1.4921071View Description Hide Description
The amyloid deposition in the form of extracellular fibrillar aggregates of amyloid-β (Aβ) peptide is a critical pathological event in Alzheimer’s disease. Here, we report a systematic investigation of the effects of environmental factors on the kinetics of Aβ fibrillization in vitro. The effects of Aβ42 peptide concentration, temperature, pH, added solvents and the ratio of Aβ40 and Aβ42 on the peptide fibrillization under agitated conditions was studied. The analysis show that the rate of fibril growth by monomer addition is not limited by diffusion but by rearrangement in the monomer structure, which is enhanced by low concentrations of fluorinated alcohols and characterized by the activation energy of 12 kcal/mol. Fibrillization rate decreases at pH values below 7.0 where simultaneous protonation of His 13 and 14 inhibits fibril formation. The lag period for Aβ42 was only twofold shorter and the fibril growth rate twofold faster than those of Aβ40. Lag period was shortened and the fibrillization rate was increased only at 90% content of Aβ42.
5(2015); http://dx.doi.org/10.1063/1.4921072View Description Hide Description
Amyloid plaques formation and oxidative stress are two key events in the pathology of the Alzheimer disease (AD), in which metal cations have been shown to play an important role. In particular, the interaction of the redox active Cu 2+ metal cation with Aβ has been found to interfere in amyloid aggregation and to lead to reactive oxygen species (ROS). A detailed knowledge of the electronic and molecular structure of Cu 2+-Aβ complexes is thus important to get a better understanding of the role of these complexes in the development and progression of the AD disease. The computational treatment of these systems requires a combination of several available computational methodologies, because two fundamental aspects have to be addressed: the metal coordination sphere and the conformation adopted by the peptide upon copper binding. In this paper we review the main computational strategies used to deal with the Cu 2+-Aβ coordination and build plausible Cu 2+-Aβ models that will afterwards allow determining physicochemical properties of interest, such as their redox potential.
- Invited Articles on Amyloid Aggregation: Characterization, Function and Molecular Mechanisms
5(2015); http://dx.doi.org/10.1063/1.4921073View Description Hide Description
Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.
Self-assembly dynamics for the transition of a globular aggregate to a fibril network of lysozyme proteins via a coarse-grained Monte Carlo simulation5(2015); http://dx.doi.org/10.1063/1.4921074View Description Hide Description
The self-organizing dynamics of lysozymes (an amyloid protein with 148 residues) with different numbers of protein chains, Nc = 1,5,10, and 15 (concentration 0.004 – 0.063) is studied by a coarse-grained Monte Carlo simulation with knowledge-based residue-residue interactions. The dynamics of an isolated lysozyme (Nc = 1) is ultra-slow (quasi-static) at low temperatures and becomes diffusive asymptotically on raising the temperature. In contrast, the presence of interacting proteins leads to concentration induced protein diffusion at low temperatures and concentration-tempering sub-diffusion at high temperatures. Variation of the radius of gyration of the protein with temperature shows a systematic transition from a globular structure (at low T) to a random coil (high T) conformation when the proteins are isolated. The crossover from globular to random coil becomes sharper upon increasing the protein concentration (i.e. with Nc = 5,10), with larger Rg at higher temperatures and concentration; Rg becomes smaller on adding more protein chains (e.g. Nc = 15) a non-monotonic response to protein concentration. Analysis of the structure factor (S(q)) provides an estimate of the effective dimension (D ≥ 3, globular conformation at low temperature, and D ∼ 1.7, random coil, at high temperatures) of the isolated protein. With many interacting proteins, the morphology of the self-assembly varies with scale, i.e. at the low temperature (T = 0.015), D ∼ 2.9 on the scale comparable to the radius of gyration of the protein, and D ∼ 2.3 at the large scale over the entire sample. The global network of fibrils appears at high temperature (T = 0.021) with D ∼ 1.7 (i.e. a random coil morphology at large scale) involving tenuous distribution of micro-globules (at small scales).
5(2015); http://dx.doi.org/10.1063/1.4921314View Description Hide Description
The relationship of copper dyshomeostasis with neurodegenerative diseases has become evident in the last years. Because of the major role that this metal ion plays in biological processes, most of which being located in the brain, it is not surprising that changes in its distribution are closely related with the advent of neurodegenerative disorders such as Alzheimer’s disease (AD). An increasing number of works have dealt with this subject in the last years, and opened an intense debate in some points while raising new questions that still remain unanswered. This revision work puts together and discusses the latest findings and insights on how copper ions are involved in AD progression, including its interaction with Aβ and its consequently induced aggregation.