Journal
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume 58, Issue 5, Pages 1053-1065Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.8b00045
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A beta 25-35 is a short, cytotoxic, and naturally occurring fragment of the Alzheimer's Afi peptide. To map the molecular mechanism of A beta 25-35 binding to the zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer, we have performed replica exchange with solute tempering molecular dynamics simulations using all-atom explicit membrane and water models. Consequences of sequence truncation on the binding mechanism have been measured by utilizing as a control our previous simulations probing binding of the longer peptide A beta 10-40 to the same bilayer. The most intriguing feature of A beta 25-35 binding to the DMPC bilayer is a coexistence of two bound states with strikingly different characteristics: a dominant surface-bound state and a less stable inserted state. In the surface-bound state, the peptide samples extended conformations, in which its unbound C-terminal is pointed away from the bilayer. In contrast, in the inserted state, the C-terminal resides deep in the bilayer hydrophobic core. In both states, the N-terminal remains anchored to the bilayer. Free energy landscape analysis reveals that the two states are separated by a moderate barrier, suggesting that A beta 25-35 monomer may frequently interconvert between them. The net effect of A beta 25-35 binding is a minor impact on the bilayer structure, which contrasts with the considerable bilayer perturbations induced by a longer A beta 10-40 peptide penetrating deep into the bilayer core. Therefore, we conclude that the binding mechanisms of A beta 25-35 and A beta 10-40 peptides are different. Potential implications of our results for A beta 25-35 cytotoxicity are discussed. A comparison of experimental data with our findings reveals a good agreement.
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