Huntington's disease is a neurodegenerative disorder caused by an expanded polyglutamine (polyQ) domain within the huntingtin protein (htt) that initiates toxic protein aggregation. Htt directly interacts with membranes, influencing aggregation and spurring membrane abnormalities. These interactions are facilitated by the 17 N-terminal residues (Nt17) that form an amphipathic α-helix implicated in both lipid binding and aggregation. Here, the impact of unsaturation in phospholipid tails on htt−lipid interaction and htt aggregation was determined. There was no correlation between the degree of htt−lipid complexation and the degree of htt aggregation in the presence of each lipid system, indicating that lipid systems with different properties uniquely alter the membrane-mediated aggregation mechanisms. Also, the association between Nt17 and membrane surfaces is determined by complementarity between hydrophobic residues and membrane defects and how easily the peptide can partition into the bilayer. Our results provide critical insights into how membrane physical properties influence downstream htt aggregation.

The pH‐Low Insertion Peptide (pHLIP) is a membrane‐active peptide that spontaneously folds into a transmembrane α‐helix upon acidification. This activity enables pHLIP to potentially act as a vector for drugs related to diseases characterized by acidosis such as cancer or heart ischemia. Presently, due to aggregation‐based effects, formulations of pHLIP are only viable at near‐μM concentrations. In addition, since most of pHLIP's measurable qualities involve a membrane, probing the details of pHLIP in the interstitial region is difficult. In attempts to shed light on these issues, we performed constant pH molecular dynamics simulations on pHLIP as well as P20G, a variant with increased helicity, in solution at 0 and 150 mM NaCl over a broad range of pHs. In general, the addition of ions reduced the effective pKa of the acidic residues in pHLIP. P20G exhibits a higher helicity than pHLIP in general and is more compact than pHLIP at pH values under 4. In terms of charge effects, sodium cations localized predominantly to the C‐terminus of the peptide with a high density of acidic residues. Additionally, the salt bridge between R11 and D14 is by far the most favored and particularly so with pHLIP at 150 mM NaCl. We expect that this approach will be a valuable tool to screen variants of pHLIP for favorable properties in solution, an aspect of pHLIP design that to this point has largely been neglected.

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Anthrax toxin channel, protective antigen (PA 63 ), is known to be strongly cation selective, the property that has determined the development of positively charged inhibitors as channel blockers. Successful interpretation of small ion transport through PA 63 can also contribute to the description of the translocase activity of the channel that transports the enzymatic factors of anthrax toxin, lethal factor (LF) and edema factor (EF), into the cytosol. It was recently suggested by Kalu et al (FEBS Letters, 2012) that PA 63 conductance is determined