For example, the b-pleated model peptide 3 can assemble as b-sheets even with one third of its amino acids exchanged to the D-form, meaning that only the D-amino acid itself and its closest neighbors are excluded from the ordered array of hydrogen-bonds in a typical sheet. It is therefore perfectly reasonable that a bulky D-amino acid can have both effects, of either preventing or promoting amyloid formation. The observed outcome depends on the relative destabilization of the original conformation compared to the Doxapram hydrochloride resulting b-sheet structure. In the case of TP10, which already contains an unstructured N-terminus, the aggregation equilibrium is shifted to the right when the destabilizing D-CF3-Bpg is incorporated into the C-terminus. In the Model Amphiphilic Peptide MAP, on the other hand, the equilibrium is shifted to the left and aggregation is prevented by a D-amino acid. That is because MAP can engage in favorable interactions with the membrane only as an amphiphilic helix. Likewise, in 3, bulky D-amino acids shift the aggregation threshold to higher peptide concentration, as the unfolded peptide has no reason to become a-helical. Based on the TEM images and the OCD spectra of aggregated TP10 with D-CF3-Bpg, which show an essentially complete bstructure, we expect that the entire peptide may assume a regular b-sheet conformation in the presence as well as absence of membranes, apart from the local position that is labeled with DCF3-Bpg and its immediate surroundings. There is of course no indication from our data on the parallel or antiparallel alignment, or any Diclofenac Diethylamine possible staggering. However, a parallel unstaggered arrangement as depicted in Figure 9C would minimize the destabilizing effects of the D-amino acid on the b-sheet and is therefore most likely. We trust that this picture offers for the first time an appropriate description of the monomeric structure of TP10 in a lipid bilayer, and of its possible conformational switch in the presence of a cellular membrane at high concentration. To our knowledge this is the first detailed study focusing on the structure analysis and aggregation propensity of a cellpenetrating peptide in its functionally relevant membrane-bound state. TP10 is a truncated derivative of transportan, a designermade hybrid that was constructed from an N-terminal galanin sequence and a C-terminal mastoparan part, as illustrated in Figure 10.