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  1. The fungus Candida albicans is the most common cause of yeast infections in humans. Like many other disease-causing microbes, it releases several virulent proteins that invade and damage human cells. This includes the peptide candidalysin which has been shown to be crucial for infection. Human cells are surrounded by a protective membrane that separates their interior from their external environment. Previous work showed that candidalysin damages the cell membrane to promote infection. However, how candidalysin does this remained unclear. Similar peptides and proteins cause harm by inserting themselves into the membrane and then grouping together to form a ring. This creates a hole, or ‘pore’, that weakens the membrane and allows other molecules into the cell’s interior. Here, Russell, Schaefer et al. show that candidalysin uses a unique pore forming mechanism to impair the membrane of human cells. A combination of biophysical and cell biology techniques revealed that the peptide groups together to form a chain. This chain of candidalysin proteins then closes in on itself to create a loop structure that can insert into the membrane to form a pore. Once embedded within the membrane, the proteins within the loops rearrange again to make the pores more stable so they can cause greater damage. This type of pore formation has not been observed before, and may open up new avenues of research. For instance, researchers could use this information to develop inhibitors that stop candidalysin from forming chains and harming the membranes of cells. This could help treat the infections caused by C. albicans. 
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  2. We demonstrated ion-mobility spectrometry mass spectrometry (IMS-MS) as a powerful tool for interrogating and preserving selective chemistry including non-covalent and host–guest complexes of m -xylene macrocycles formed in solution. The technique readily revealed the unique favorability of a thiourea-containing macrocycle MXT to Zn 2+ to form a dimer complex with the cation in an off-axis sandwich structure having the Zn–S bonds in a tetrahedral coordination environment. Replacing thiourea with urea generates MXU which formed high-order oligomerization with weak binding interactions to neutral DMSO guests detected at every oligomer size. The self-assembly pathway observed for this macrocycle is consistent with the crystalline assembly. Further transformation of urea into squaramide produces MXS, a rare receptor for probing sulfate in solution. Tight complexes were observed for both monomeric and dimeric of MXS in which HSO 4 − bound stronger than SO 4 2− to the host. The position of HSO 4 − at the binding cavity is a 180° inversion of the reported crystallographic SO 4 2− . The MXS dimer formed a prism-like shape with HSO 4 − exhibiting strong contacts with the 8 amine protons of two MXS macrocycles. By eliminating intermolecular interferences, we detected the low energy structures of MXS with collisional cross section (CCS) matching cis – trans and cis – cis squaramides-amines, both were not observed in crystallization trials. The experiments collectively unravel multiple facets of macrocycle chemistry including conformational flexibility, self-assembly and ligand binding; all in one analysis. Our findings illustrate an inexpensive and widely applicable approach to investigate weak but important interactions that define the shape and binding of macrocycles. 
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  3. Despite being relatively benign and not an indicative signature of toxicity, fibril formation and fibrillar structures continue to be key factors in assessing the structure–function relationship in protein aggregation diseases. The inability to capture molecular cross-talk among key players at the tissue level before fibril formation greatly accounts for the missing link toward the development of an efficacious therapeutic intervention for Type II diabetes mellitus (T2DM). We show that human α-calcitonin gene-related peptide (α-CGRP) remodeled amylin fibrillization. Furthermore, while CGRP and/or amylin monomers reduce the secretion of both mouse Ins1 and Ins2 proteins, CGRP oligomers have a reverse effect on Ins1. Genetically reduced Ins2, the orthologous version of human insulin, has been shown to enhance insulin sensitivity and extend the life-span in old female mice. Beyond the mechanistic insights, our data suggest that CGRP regulates insulin secretion and lowers the risk of T2DM. Our result rationalizes how migraine might be protective against T2DM. We envision the new paradigm of CGRP : amylin interactions as a pivotal aspect for T2DM diagnostics and therapeutics. Maintaining a low level of amylin while increasing the level of CGRP could become a viable approach toward T2DM prevention and treatment. 
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  4. Proteins and peptides in nature are almost exclusively made from l -amino acids, and this is even more absolute in the metazoan. With the advent of modern bioanalytical techniques, however, previously unappreciated roles for d -amino acids in biological processes have been revealed. Over 30 d -amino acid containing peptides (DAACPs) have been discovered in animals where at least one l -residue has been isomerized to the d -form via an enzyme-catalyzed process. In Aplysia californica , GdFFD and GdYFD (the lower-case letter “d” indicates a d -amino acid residue) modulate the feeding behavior by activating the Aplysia achatin-like neuropeptide receptor (apALNR). However, little is known about how the three-dimensional conformation of DAACPs influences activity at the receptor, and the role that d -residues play in these peptide conformations. Here, we use a combination of computational modeling, drift-tube ion-mobility mass spectrometry, and receptor activation assays to create a simple model that predicts bioactivities for a series of GdFFD analogs. Our results suggest that the active conformations of GdFFD and GdYFD are similar to their lowest energy conformations in solution. Our model helps connect the predicted structures of GdFFD analogs to their activities, and highlights a steric effect on peptide activity at position 1 on the GdFFD receptor apALNR. Overall, these methods allow us to understand ligand–receptor interactions in the absence of high-resolution structural data. 
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