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Protein-membrane interactions underlie numerous biological processes including folding of ion channels and signal transduction across lipid membranes. A detailed understanding of protein-lipid interactions is critical for designing membrane-active peptides as potential antibiotics, as well. Using gramicidin A (gA) as a model system, we investigated the effects of lysine methylation on peptide folding into transmembrane channels. The results are discussed in terms of the peptides' binding affinity to, translocation across, and structure formation in lipid membranes. The results show that gA mutants with N(ɛ)-trimethylated D-lysines (dMe3 K) are capable of folding into wild type-like channels that are selective for monovalent cations. Surprisingly, N(ɛ)-trimethylation in general reduces the peptide's binding affinity to lipid membranes despite the increased hydrophobicity. Further investigation reveals the critical contribution of the hydrogen bonding potential of lysine side chains to peptide-membrane association, which has previously been underappreciated. Importantly, methylation does give improved therapeutic indices for certain combinations of gA variant and bacterium, indicating that methylation can be an effective strategy to fine tune the performance of peptide antibiotics.

Fluorinated amino acids serve as powerful tools in protein chemistry. We synthesized a series of para-substituted tetrafluorophenylalanines via the regioselective S(NAr) chemistry of the commercially available pentafluorophenylalanine Boc-Z. These novel unnatural amino acids display distinct (19)F NMR signatures, making them powerful tools for analyzing protein-membrane interactions with NMR spectroscopy.

(Diacetoxyiodo)benzene (PhI(OAc) 2 ) was found to be a powerful reagent to induce the intramolecular oxidative bromocyclization of homoallylic sulfonamides utilizing KBr as the bromine source. The reaction affords 2-substituted-4-bromo-pyrrolidines in moderate to excellent yields under a mild metal-free condition, and offers good manipulability by avoiding the use of highly toxic and caustic bromine (Br 2 ).

A highly efficient, three-component one-pot benzylation and allylation of aromatic and aliphatic aldehydes and amines affords the corresponding homobenzylamines and homoallylamines in good to excellent yield. The procedure is lauded by its simplicity and manipulability.

Protein-membrane interactions underlie numerous biological processes including folding of ion channels and signal transduction across lipid membranes. A detailed understanding of protein-lipid interactions is critical for designing membrane-active peptides as potential antibiotics, as well. Using gramicidin A (gA) as a model system, we investigated the effects of lysine methylation on peptide folding into transmembrane channels. The results are discussed in terms of the peptides' binding affinity to, translocation across, and structure formation in lipid membranes. The results show that gA mutants with N(ɛ)-trimethylated D-lysines (dMe3 K) are capable of folding into wild type-like channels that are selective for monovalent cations. Surprisingly, N(ɛ)-trimethylation in general reduces the peptide's binding affinity to lipid membranes despite the increased hydrophobicity. Further investigation reveals the critical contribution of the hydrogen bonding potential of lysine side chains to peptide-membrane association, which has previously been underappreciated. Importantly, methylation does give improved therapeutic indices for certain combinations of gA variant and bacterium, indicating that methylation can be an effective strategy to fine tune the performance of peptide antibiotics.

"Smart" peptides that lyse membranes in response to biological stimuli are of considerable interest. Herein, we report a facile synthesis of L-tetrafluorotyrosine (L-f(4)Y) and its utilization as a pH sensing element. The synthetic route affords gram quantities of L-f(4)Y within two days. Incorporation of this unnatural amino acid into magainin 2 gives a peptide that turns on its membrane-lytic activity upon mild acidification.

Fluorescent molecules that specifically target amyloid structures are highly desirable for amyloid research. Herein, we show a dimeric design of thioflavin T improves its binding affinity to Abeta amyloid by up to 70 fold, while not sacrificing the specificity and the "light-up" feature upon amyloid binding.

(Diacetoxyiodo)benzene (PhI(OAc) 2 ) was found to be a powerful reagent to induce the intramolecular oxidative bromocyclization of homoallylic sulfonamides utilizing KBr as the bromine source. The reaction affords 2-substituted-4-bromo-pyrrolidines in moderate to excellent yields under a mild metal-free condition, and offers good manipulability by avoiding the use of highly toxic and caustic bromine (Br 2 ).