Alzheimer’s Aβ10–40 Peptide Binds and Penetrates DMPC Bilayer: An Isobaric–Isothermal Replica Exchange Molecular Dynamics Study

Abstract

Using all-atom explicit solvent model and isobaric-isothermal replica exchange molecular dynamics, we studied binding of Aβ10-40 monomers to zwitterionic DMPC bilayer. Our simulations suggest three main conclusions. First, binding of Aβ10-40 monomer to the DMPC bilayer causes dramatic structural transition in the peptide resulting in the formation of stable helical structure in the C-terminal. In addition, binding to the lipid bilayer induces the formation of intrapeptide Asp23-Lys28 salt bridge. We argue that the emergence of helix is the consequence of hidden helix propensity harbored in the Aβ10-40 C-terminal. This propensity is revealed by the lipids cross-bridging amino acids in helical conformations and by significant hydrophobic moment of the C-terminal. Second, the central hydrophobic cluster and, particularly, the C-terminal of Aβ10-40 not only govern binding to the bilayer but also penetrate into bilayer core. In contrast, the polar N-terminal and turn region form interactions mainly with the bilayer surface. Third, our simulations suggest that upon Aβ10-40 binding to the bilayer a highly heterogeneous local environment emerges along Aβ10-40 chain. The N-terminal is exposed to polar well-hydrated medium, whereas the C-terminal is largely shielded from water residing in mostly hydrophobic environment. The implication of our results is that Aβ aggregation mediated by zwitterionic lipid bilayer is likely to be different from that in bulk water.

Replica exchange molecular dynamics study of the amyloid beta (11–40) trimer penetrating a membrane

“…These two domains correspond to the stable and uctuating regions of the oligomer, respectively. This nding is in agreement with both previous experimental 24,26,27,46 and computational [28][29][30][31][32][33] studies. We hope that new knowledge of these structures can enhance the search for an Ab therapy.…”

“…27 These experimental results were analyzed and supported by numerous subsequent theoretical studies. [28][29][30][31][32][33] Due to the fact that the Ab trimer is one of the most toxic forms of low weight oligomers, 34 current studies are focused on screening potential inhibitors to prevent the trimer from forming. 35 However, the equilibrated Ab trimers exist in mixed environments consisting of monomers, dimers, higher order oligomers and mature brils; thus, experimental studies about them are few.…”

“…In accord with previous experiments and computations, the secondary structure of the oligomer has been predicted using the Dene Secondary Structure of Proteins (DSSP) tool; a-content was lacking during our simulations, while the b-content and statistical coil structures comprised about 40% and 60% of the structure, respectively. 24,[26][27][28][29][30][31][32][33]46 The coil domains are located within the membrane surface and strongly interact with the phosphorus atoms of the lipid headgroups. 24,26 The Asp23-Asn27 salt bridge was found to play an important role in stabilizing the structure of the Ab peptide, instead of the Asp23-Lys28 salt bridge, as previously reported.…”

Trp-Cage Folding on Organic Surfaces

“…29 The latter technique significantly dampens proper membrane motion and fluidity, thereby perturbing the conformational landscape of Trp-cage near a membrane's surface. The former techniques, however, are the basis for MetaD simulations, though these additional degrees of freedom must be carefully selected to minimally disrupt nearby interfaces.…”

Enhanced sampling techniques in molecular dynamics simulations of biological systems

“…From the initial application of REMD to the penta-peptide met-enkephalin [24], to more recent efforts where improved forms of the method were developed, such as constant pH replica exchange [25] or isobaric-isothermal REMD to study Alzheimer’s peptides [26], REMD has gained ground and proven to be effective under a broad range of contexts. Applications of REMD have been shown to agree with MD results and as long as there is a positive activation energy for folding, REMD was shown to be more efficient than MD [27].…”