Folding Then Binding vs Folding Through Binding in Macrocyclic Peptide Inhibitors of Human Pancreatic α-Amylase

De novo macrocyclic peptides, derived using selection technologies such as phage and mRNA display, present unique and unexpected solutions to challenging biological problems. This is due in part to their unusual folds, which are able to present side chains in ways not available to canonical structures such as α-helices and β-sheets. Despite much recent interest in these molecules, their folding and binding behavior remains poorly characterized. In this work, we present cocrystallization, docking, and solution NMR structures of three de novo macrocyclic peptides that all bind as competitive inhibitors with single-digit nanomolar K i to the active site of human pancreatic α-amylase. We show that a short stably folded motif in one of these is nucleated by internal hydrophobic interactions in an otherwise dynamic conformation in solution. Comparison of the solution structures with a target-bound structure from docking indicates that stabilization of the bound conformation is provided through interactions with the target protein after binding. These three structures also reveal a surprising functional convergence to present a motif of a single arginine sandwiched between two aromatic residues in the interactions of the peptide with the key catalytic residues of the enzyme, despite little to no other structural homology. Our results suggest that intramolecular hydrophobic interactions are important for priming binding of small macrocyclic peptides to their target and that high rigidity is not necessary for high affinity

Haskell Gets Argumentative

Abstract. Argumentation theory is an interdisciplinary field studying how conclusions can be reached through logical reasoning. The notion of argument is completely general, including for example legal arguments, scientific arguments, and political arguments. Computational argumentation theory is studied in the context of artificial intelligence, and a number of computational argumentation frameworks have been put forward to date. However, there is a lack of concrete realisations of these frameworks, which hampersresearch andapplications at anumberoflevels. We hypothesise that the lack of suitable domain-specific languages in which to formalise argumentation frameworks is a contributing factor. In this paper, we present a formalisation of a particular computational argumentation framework, Carneades, as a case study with a view to investigate the extent to which functional languages are useful as a means to realising computational argumentation frameworks and reason about them