The Molecular Modeling Core enjoys a long-standing collaboration with Dr. Robert Guy's section in the Lab of Cell Biology. We have taken an evolutionary approach to the study of ion channel proteins, examining the structural changes that accompanied the development of Na+ and Ca2+ channels from K+ channels by making representative models of each subfamily. These last two years, we have also focused on modeling the aqueous-soluble and ion channel structures formed by the Amyloid-Beta Peptide (ABP) associated with Alzheimer's Disease (AD). While it used to be thought that AD was caused by large fibril structures, numerous recent studies now indicate that the inhibition of long-term potentiation responsible for short-term memory loss, and the neurotoxicity responsible for cell death, are due to smaller oligomeric assemblies of the peptides. Recent studies also indicate that the neurotoxity involves interactions of the oligomers with membranes and that ABP indeed forms transmembrane ion channels. Unfortunately, direct experimental determination has been hampered by the fact that both aqueous and membrane-bound oligomeric structures of ABP are very sensitive to the specifics of the environment, and change over time. This last year, our efforts have resulted in two publications that model the progressive development of ABP assemblies in aqueous solution and cell membranes, consistent with numerous experimental results. Both soluble and membrane-bound pre-fibrillar assemblies of ABP have been associated with AD. The size and nature of these assemblies vary greatly and are affected by many factors. In the first paper we present models of water-soluble hexameric assemblies of ABP42, and suggest how they can lead to larger assemblies and eventually to fibrils. The common element in most of these assemblies is a six-stranded beta-barrel formed by the last third of ABP42, which is composed of hydrophobic residues and glycines. The hydrophobic core beta-barrels of the hexameric models are shielded from water by the N-terminus and central segments. These more hydrophilic segments were modeled to have either predominantly beta or predominantly alpha secondary structure. Molecular dynamics simulations were performed to analyze the stabilities of the models. The hexameric models were used as starting points from which larger soluble assemblies of 12 and 36 subunits were modeled. While it is clear that ABP assemblies play a pivotal role in the development of AD, the precise molecular mode of action remains unclear. Some experimental evidence indicates that deleterious effects occur when the peptides interact with membranes, possibly by forming Ca2+ permeant ion channels. In the second paper we explore how the aqueous-soluble assemblies of the first paper could bind to membranes and develop into channel structures. In these models, the hydrophobic beta-barrel of a hexamer may either reside on the surface or span the bilayer. Transmembrane pores are proposed to form between several hexamers. Once the beta-barrels of six hexamers have spanned the bilayer, they may merge to form a more stable 36-stranded beta-barrel. We favor models in which parallel beta-barrels formed by N-terminus segments comprise the lining of the pores. These types of models explain why the channels are selective for cations and how metal ions, such as Zn2+, and some small organic cations may block channels or inhibit their formation. These models were also guided by being consistent with new microscopy studies of ABP assemblies in membranes that were also included in this paper. This year we also published a third, related paper, which was a direct collaboration with experimentalists to model the interaction of an inhibitor with ABP ion channels. The four-histidine peptide, NAHis04, potently blocks the intracellular calcium increase which is observed in PC12 cells exposed to ABP. Working from our models in the second paper, we show structurally how up to four NAHis04 peptides may block these types of pores by binding to the Glu 11, His 13, and His 14 side chains of the ABP channel residues.