Oligomers formed by amyloid β-protein (Aβ) are central to Alzheimer's disease (AD) pathology, yet their structure remains elusive. Of the two predominant Aβ alloforms, Aβ40 and Aβ42, the latter is more strongly associated with AD. Here, we structurally characterized Aβ40 and Aβ42 monomers through pentamers which were converted from previously derived coarse-grained (DMD4B-HYDRA) simulations into all-atom conformations and subjected to explicit-solvent MD. Free energy landscapes revealed that structural differences between Aβ40 and Aβ42 conformations increase with oligomer order up to trimers. All conformations display high statistical coil and turn content (40-50%) with minor β-strand and α-helical content (<10%). Aβ40 tetramers and pentamers exhibit significantly more elongated morphologies than the respective Aβ42 conformations. Unlike the initial DMD4B-HYDRA conformations, fully atomistic Aβ40 and Aβ42 trimers, tetramers, and pentamers form water-permeable pores, whereby the tendency for pore formation sharply increased with oligomer order and is the highest for Aβ42 pentamers. Previous studies reported that Aβ oligomers form ion channels when embedded into a cellular membrane, which causes an abnormal ion flux and eventually leads to cell death. Our findings reveal an extraordinary ability of Aβ oligomers to form pores in pure water prior to their insertion into a membrane and thus provide support to the ion channel hypothesis of AD.

and unfavorable enthalpy, respectively. Furthermore, we characterize dock and lock states of the peptide based on the solvent accessible surface area. We observe that the Lennard-Jones energy of the system increases continuously in lock and dock states as the peptide dissociates. The electrostatic energy in the lock state increases as the peptide dissociates and inter-peptide hydrogen bonds are ruptured while it decreases in the dock state as new peptide-water hydrogen bonds are formed. We also observe that before unbinding from the fibril, the peptide has to overcome an enthalpic barrier of the order of 10 kJmol À1 . This barrier is associated to interactions between exposed phenylalanine residues of the fibril and the peptide. Implication of these results to fibril growth will be discussed. 2656-Pos Board B86A Computational Study of Amyloid b-Protein Assembly in Crowded Environments Matthew J. Voelker, Brigita Urbanc, Mark Betnel. Physics, Drexel University, Philadelphia, PA, USA. Alzheimer's disease is strongly associated with aberrant amyloid b-protein (Ab) assembly into heterogeneous, metastable oligomeric assemblies with structures that have not been experimentally characterized yet. The 40 and 42 amino acids long Ab40 and Ab42 are the two predominant Ab alloforms in the brain. Whereas Ab40 and Ab42 oligomer formation from monomeric state is still inaccessible to fully atomistic explicit-solvent molecular dynamics, Ab40 and Ab42 oligomers were structurally characterized using discrete molecular dynamics (DMD) and an intermediate-resolution protein model within the DMD4B-HYDRA implicit solvent force field, and the corresponding oligomer size distributions well matched the available in vitro data. In vivo, however, Ab coexists with other biomolecules in a rather crowded environment. To understand the effect of crowding on Ab oligomer formation, we used the DMD4B-HYDRA force field and added to an ensemble of 32 monomeric Ab40 or Ab42 peptides inert spherical ''crowders'' with a diameter of 0.5 nm at various concentrations to examine their effect on Ab40 and Ab42 oligomerization pathways. Our results show that crowding shifts oligomer size distributions towards smaller oligomer sizes and increases solubility of both peptides in a concentration-dependent way. The effect is stronger for Ab42, where crowding abolishes the multimodal character of the oligomer size distribution. Our structural analysis revealed that the stability of larger oligomers is compromised by effective osmotic pressure exerted by the crowders, resulting in an increased rate of assembly breakage. While in vivo crowding agents are not inert as the crowders in our study, we here reveal that crowding-induced osmotic pressure strongly affects protein assembly dynamics, which is of significance to the disease. 2657-Pos Board B87Transition of Amyloid Oligomers to Mature Fibrils: Internal Conversion Vs. Competing Assembly Pathways? Tatiana Miti, Mentor Mulaj, Martin Muschol. physics, University of south Florida, tampa, FL, USA. Deposition of protein...

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