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.

We have applied replica exchange with solute tempering (REST) molecular dynamics to study a short fragment of the Aβ peptide, Aβ25-35, in water and a much larger system incorporating two Aβ10-40 peptides binding to the zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer. As a control, we used traditional replica exchange molecular dynamics (REMD) applied to the same systems. Our objective was to assess the practical utility of REST simulations. Taken together, our results suggest four conclusions. First, compared to REMD, the number of replicas in REST simulations can be reduced four to five times without affecting the temperature range or compromising an efficient random walk of REST replicas over temperatures. Second, although overall REST produces much fewer conformational states than REMD, there is no substantial difference in the collection of unique states for the wild-type replica in REST and REMD, especially for the system featuring Aβ peptides binding to the lipid bilayer. Third, we performed a thorough comparison of REST and REMD equilibrium conformational ensembles, including thermal averages and probability distributions. REST reproduces REMD data extremely well for the system of Aβ peptides binding to the DMPC lipid bilayer. The agreement between REST and REMD equilibrium sampling of Aβ25-35 in water is less perfect, but it improves with addition of new REST simulations. Surprisingly, REST demonstrates much better convergence for the system featuring ordered peptides binding to lipid bilayer rather than for a small unstructured peptide solvated in water. Fourth, REST delivers its full computational advantage over REMD when applied to peptides interacting with lipid bilayers. For peptides solvated in water, REST does not appear to offer computational gain but may make replica simulations practically feasible due to a lower requirement for parallel computing environments. Our study is expected to facilitate wider application of REST in biomolecular simulations.

Using isobaric-isothermal replica exchange molecular dynamics and all-atom explicit water model we study the impact of Aβ monomer binding on the equilibrium properties of DMPC bilayer. We found that partial insertion of Aβ peptide into the bilayer reduces the density of lipids in the binding "footprint" and indents the bilayer thus creating a lipid density depression. Our simulations also reveal thinning of the bilayer and a decrease in the area per lipid in the proximity of Aβ. Although structural analysis of lipid hydrophobic core detects disordering in the orientations of lipid tails, it also shows surprisingly minor structural perturbations in the tail conformations. Finally, partial insertion of Aβ monomer does not enhance water permeation through the DMPC bilayer and even causes considerable dehydration of the lipid-water interface. Therefore, we conclude that Aβ monomer bound to the DMPC bilayer fails to perturb the bilayer structure in both leaflets. Limited scope of structural perturbations in the DMPC bilayer caused by Aβ monomer may constitute the molecular basis of its low cytotoxicity.

Using all-atom explicit water model and replica exchange molecular dynamics, we study the interactions between Aβ monomer and nonsteroidal anti-inflammatory drug ibuprofen, which is known to reduce the risk of Alzheimer's disease. Ibuprofen binding to Aβ is largely governed by hydrophobic effect, and its binding site in Aβ peptide is entirely composed of hydrophobic amino acids. Electrostatic interactions between negatively charged ibuprofen ligands and positively charged side chains make a relatively small contribution to binding. This outcome is explained by the competition of ligand-peptide electrostatic interactions with intrapeptide salt bridges. Consistent with the experiments, the S-isomer of ibuprofen binds with stronger affinity to Aβ than the R-isomer. Conformational ensemble of Aβ monomer in ibuprofen solution reveals two structured regions, 19-25 (R1) and 29-35 (R2), composed of turn/helix and helix structure, respectively. The clustering technique and free energy analysis suggest that Aβ conformational ensemble is mainly determined by the formation of Asp23-Lys28 salt bridge and the hydrophobic interactions between R1 and R2. Control simulations of Aβ peptide in ligand-free water show that ibuprofen binding changes Aβ structure by promoting the formation of helix and Asp23-Lys28 salt bridge. Implications of our findings for Aβ amyloidogenesis are discussed.

All-atom explicit solvent model and replica exchange molecular dynamics were used to investigate binding of Alzheimer's biomarker FDDNP to the Aβ(10-40) monomer. At low and high concentrations, FDDNP binds with high affinity to two sites in the Aβ(10-40) monomer located near the central hydrophobic cluster and in the C-terminal. Analysis of ligand- Aβ(10-40) interactions at both concentrations identifies hydrophobic effect as a main binding factor. However, with the increase in ligand concentration the interactions between FDDNP molecules also become important due to strong FDDNP self-aggregation propensity and few specific binding locations. As a result, FDDNP ligands partially penetrate the core of the Aβ(10-40) monomer, forming large self-aggregated clusters. Ligand self-aggregation does not affect hydrophobic interactions as a main binding factor or the location of binding sites in Aβ(10-40). Using the Aβ(10-40) conformational ensemble in ligand-free water as reference, we show that FDDNP induces minor changes in the Aβ(10-40) secondary structure at two ligand concentrations studied. At the same time, FDDNP significantly alters the peptide tertiary fold in a concentration-dependent manner by redistributing long-range, side-chain interactions. We argue that because FDDNP does not change Aβ(10-40) secondary structure, its antiaggregation effect is likely to be weak. Our study raises the possibility that FDDNP may serve as a biomarker of not only Aβ fibril species, but of monomers as well.