Effects of the Arctic (E22-->G) mutation on amyloid beta-protein folding: discrete molecular dynamics study

• Published in: Journal of the American Chemical Society Vol. 130; no. 51; pp. 17413 - 17422
• Main Authors: Lam, A R, Teplow, D B, Stanley, H E, Urbanc, B
• Format: Journal Article
• Language: English
• Published: United States 24.12.2008
• Subjects: Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; Animals; Circular Dichroism; Computer Simulation; Drug Design; Humans; Hydrogen Bonding; Models, Statistical; Mutation; Neurons - metabolism; Peptides - chemistry; Protein Conformation; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja804984h

The 40-42 residue amyloid beta-protein (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD). Of the two main alloforms, Abeta40 and Abeta42, the longer Abeta42 is linked particularly strongly to AD. Despite the relatively small two amino acid length difference in primary structure, in vitro studies demonstrate that Abeta40 and Abeta42 oligomerize through distinct pathways. Recently, a discrete molecular dynamics (DMD) approach combined with a four-bead protein model recapitulated the differences in Abeta40 and Abeta42 oligomerization and led to structural predictions amenable to in vitro testing. Here, the same DMD approach is applied to elucidate folding of Abeta40, Abeta42, and two mutants, [G22]Abeta40 and [G22]Abeta42, which cause a familial ("Arctic") form of AD. The implicit solvent in the DMD approach is modeled by amino acid-specific hydropathic and electrostatic interactions. The strengths of these effective interactions are chosen to best fit the temperature dependence of the average beta-strand content in Abeta42 monomer, as determined using circular dichroism (CD) spectroscopy. In agreement with these CD data, we show that at physiological temperatures, the average beta-strand content in both alloforms increases with temperature. Our results predict that the average beta-strand propensity should decrease in both alloforms at temperatures higher than approximately 370 K. At physiological temperatures, both Abeta40 and Abeta42 adopt a collapsed-coil conformation with several short beta-strands and a small (<1%) amount of alpha-helical structure. At slightly above physiological temperature, folded Abeta42 monomers display larger amounts of beta-strand than do Abeta40 monomers. At increased temperatures, more extended conformations with a higher amount of beta-strand (approximately < 30%) structure are observed. In both alloforms, a beta-hairpin at A21-A30 is a central folding region. We observe three additional folded regions: structure 1, a beta-hairpin at V36-A42 that exists in Abeta42 but not in Abeta40; structure 2, a beta-hairpin at R5-H13 in Abeta42 but not in Abeta40; and structure 3, a beta-strand A2-F4 in Abeta40 but not Abeta42. At physiological temperatures, the Arctic mutation, E22G, disrupts contacts in the A21-A30 region of both [G22]Abeta peptides, resulting in a less stable main folding region relative to the wild type peptides. The Arctic mutation induces a significant structural change at the N-terminus of [G22]Abeta40 by preventing the formation of structure 3 observed in Abeta40 but not Abeta42, thereby reducing the structural differences between [G22]Abeta40 and [G22]Abeta42 at the N-terminus. [G22]Abeta40 is characterized by a significantly increased amount of average beta-strand relative to the other three peptides due to an induced beta-hairpin structure at R5-H13, similar to structure 2. Consequently, the N-terminal folded structure of the Arctic mutants closely resembles the N-terminal structure of Abeta42, suggesting that both Arctic Abeta peptides might assemble into structures similar to toxic Abeta42 oligomers.