Conformational transition of amyloid β-peptide

Abstract

The amyloid ␤-peptides (A␤s), containing 39 -43 residues, are the key protein components of amyloid deposits in Alzheimer's disease. To structurally characterize the dynamic behavior of A␤40, 12 independent long-time molecular dynamics (MD) simulations for a total of 850 ns were performed on both the wide-type peptide and its mutant in both aqueous solution and a biomembrane environment. In aqueous solution, an ␣-helix to ␤-sheet conformational transition for A␤40 was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with ␤-sheet components were observed as intermediates in the unfolding pathway of A␤40. Four glycines (G25, G29, G33, and G37) are important for A␤40 to form ␤-sheet in aqueous solution; mutations of these glycines to alanines almost abolished the ␤-sheet formation and increased the content of the helix component. In the dipalmitoyl phosphatidylcholine (DPPC) bilayer, the major secondary structure of A␤40 is a helix; however, the peptide tends to exit the membrane environment and lie down on the surface of the bilayer. The dynamic feature revealed by our MD simulations rationalized several experimental observations for A␤40 aggregation and amyloid fibril formation. The results of MD simulations are beneficial to understanding the mechanism of amyloid formation and designing the compounds for inhibiting the aggregation of A␤ and amyloid fibril formation. molecular dynamics simulation A lzheimer's disease (AD), a neurodegenerative disorder, is pathologically characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles in the brain (1). The major components of the plaques are amyloid ␤-peptides (A␤s) consisting of 39-43 residues that are proteolytically derived from the widely distributed transmembrane amyloid precursor glycoprotein (APP) (2-4). The amyloid hypothesis suggests that misfolding of A␤ leads to its dysfunctions and fibrillization; the latter is associated with a cascade of neuropathogenetic events to produce the cognitive and behavioral decline hallmarks of AD (4-6). Recently, however, compelling evidence has emerged that not the fibrillar aggregates but the dominant ␤-sheet structure of oligomers and fibril intermediates (protofibrils) are neurotoxic and might be the determinant pathogenic factor in AD (7-9). For example, Walsh et al. (8) demonstrated that cerebral microinjection of cell medium containing abundant A␤ monomers and oligomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation in rats in vivo. The conflict between the amyloid hypothesis and these new emerging experimental observations has stimulated more and more researchers to study the earliest phases of A␤ assembly and to explore the intrinsic properties of A␤s and the conformational dynamic behaviors of the A␤ monomer (9-15).In addition, it has been established experimentally that the major secondary structure adopted by A␤ depends on the environment. The A␤ monomer favors an ␣-helix structure in a me...

Computer Simulations of Alzheimers Amyloid β-Protein Folding and Assembly

“…Results of this study showed that a folded A (1-42) monomer, but not A (1-40) monomer, possesses a turn at G37-G38 stabilized by a hydrophobic interaction between V36 and V39 [94]. This turn structure is in agreement with the solution 1 One of the most extensive all-atom MD studies of helixto-coil conformational change in A (1-40) monomer was reported by Xu et al, who studied A (1-40) folding in both aqueous and membrane-like environments [96]. In an aqueous solution, A (1-40) trajectories showed an -helix -sheet and a -sheet random coil conformational change.…”

Lipid composition influences the release of Alzheimer's amyloid β‐peptide from membranes

“…All previous MD studies of Ab in membranes 17,18,27,36,[39][40][41] have consisted of only a single lipid type or an implicit model representing a membrane. In this work, however, we have explored numerous explicit model membranes, including the most complex lipid environments in which Ab has been simulated to date, rafts that correspond very closely to the lipid matrix that Ab encounters upon its production following c-secretase cleavage of APP.…”

“…In one instance (simulation GM1-CI-5), a hairpin formed involving residues Val24-Gly25 and Lys28-Gly29, connected by a turn involving Ser26-Asn27. Formation of b-strand structures near glycines within residues 24-37 has previously been proposed as an important factor in the overall conversion of Ab from a-helix to bstrand, 27 but emergence of such structures has never before been observed in simulations of membrane-bound Ab, indicating that this behavior is related to the presence of a suitable hydrogen-bond donor/acceptor environment, such as GM1 or POPE, as we observed above in the case of simulation PC/ PE-CH-3. This phenomenon is discussed in greater detail below.…”

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

“…This peptide is produced by the proteolytic cleavage of the amyloid precursor protein by the b-and c-secretases to predominantly form 40-42 amino acid peptides [4]. In its native soluble state, the peptide adopts both helical and random-coil conformations [5]. Assembly of Ab monomers leads to soluble aggregates, namely oligomers, presenting b-structure [6].…”