Linking folding with aggregation in Alzheimer's β-amyloid peptides

Abstract

Growing evidence suggests that the ␤-amyloid (A␤) peptides of Alzheimer's disease are generated in early endosomes and that small oligomers are the principal toxic species. We sought to understand whether and how the solution pH, which is more acidic in endosomes than the extracellular environment, affects the conformational processes of A␤. Using constant pH molecular dynamics simulations of two model peptides, A␤(1-28) and A␤(10 -42), we found that the folding landscape of A␤ is strongly modulated by pH and is most favorable for hydrophobically driven aggregation at pH 6. Thus, our theoretical findings substantiate the possibility that A␤ oligomers develop intracellularly before secretion into the extracellular milieu, where they may disrupt synaptic activity or act as seeds for plaque formation.␤-turn ͉ helix ͉ pH-dependent ͉ molecular dynamics ͉ electrostatics P rotein aggregation and fibril formation have been implicated in a number of human diseases, including amyloidoses and neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) that are most prevalent in aged populations. Although it is now widely known that the initial aggregation step for globular proteins involves the formation of a partially unfolded monomeric intermediate (1), little is understood for natively unfolded proteins such as the ␤-amyloid (A␤) peptides of AD and the ␣-synuclein protein of PD. To elucidate the conformational behavior of A␤, fragments as well as the full-length (40 or 42 residues) monomers have been intensively studied by spectroscopic techniques such as circular dichroism (CD) and solution NMR in both water and aqueous solutions of TFE, a cosolvent known to stabilize local hydrogen bonding in peptides with intrinsic helix propensity (2). In water, A␤ peptides have been characterized as mainly unfolded (3, 4) whereas in TFE solution, they display a pH-dependent helix profile with a minimum helix content centered around pH 5.5 (3). An early study showed that A␤(1-28) forms mature fibrils only in the pH range between 3 and 8 (5). A recent kinetics experiment revealed that the full-length A␤ aggregates most rapidly at pH 4-5.7 (6). However, conformational transitions in the early aggregation step as well as its relationship to pH remain unknown. Understanding the role of environmental conditions such as solution pH in the oligomerization of A␤ is important, because increasing experimental data suggest that A␤ is cleaved from the amyloid precursor protein in early endosomes, which have a pH of Ϸ6 (7,8) and that dimers and trimers are necessary and sufficient to disrupt synaptic activity (9, 10).We have recently developed the continuous constant pH molecular dynamics (CPHMD) method (11, 12), which allows conformational dynamics to be microscopically coupled with protonation equilibria in the atomic-level simulation of biological macromolecules. Combined with a state-of-the-art conformational sampling protocol, the replica-exchange (REX) algorithm (13), and an improved continuum solvent model (1...

Naturally Occurring Autoantibodies against β-Amyloid: Investigating Their Role in Transgenic Animal andIn VitroModels of Alzheimer's Disease

“…It was further suggested that small A␤ oligomers may form intracellularly before being released into the extracellular medium, in which they may interfere with synaptic activity or act as seeds to accelerate fibril formation (Selkoe, 2004;Khandogin and Brooks, 2007). Thus, preventing or reversing the formation of aggregated amyloid would appear to be a promising strategy for AD treatment.…”

Charge-leveling and proper treatment of long-range electrostatics in all-atom molecular dynamics at constant pH

“…[6][7][8] Among these methods, the continuous pH molecular dynamics (pHMD) method 7,8 based on λ dynamics, 9 which will be referred to as CpHMD hereafter, has been successfully applied to pK a predictions 10 and pH-dependent protein folding 11 and conformational dynamics. 12,13 The first version of the CpHMD technique makes use of the generalized Born (GB) implicit-solvent model for propagating both conformational and titration coordinates and the temperature-based a) Present address: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, USA. E-mail: jshen@rx.umaryland.edu.…”

Some Critical Aspects of Molecular Interactions Between Drugs and Receptors

“…This observation, together with more efficient pKa prediction methods (e.g. [73]) and the emergence of constant pH molecular dynamics simulations [74][75][76][77][78][79][80] to model the protonation-dependent structural changes will spark more experimental and theoretical work in pH effects on protein-protein binding.…”