Effects of Single α‑to‑β Residue Replacements on Structure and Stability in a Small Protein: Insights from Quasiracemic Crystallization

Synthetic peptides that contain backbone modifications but nevertheless adopt folded structures similar to those of natural polypeptides are of fundamental interest and may provide a basis for biomedical applications. Such molecules can, for example, mimic the ability of natural prototypes to bind to specific target macromolecules but resist degradation by proteases. We have previously shown that oligomers containing mixtures of α- and β-amino acid residues (“α/β-peptides”) can mimic the α-helix secondary structure, and that properly designed α/β-peptides can bind to proteins that evolved to bind to α-helical partners. Here we report fundamental studies that support the long-range goal of extending the α/β approach to tertiary structures. We have evaluated the impact of single α → β modifications on the structure and stability of the small and well-studied villin headpiece subdomain (VHP). The native state of this 35-residue polypeptide contains several α-helical segments packed around a small hydrophobic core. We examined α → β substitution at four solvent-exposed positions, Asn19, Trp23, Gln26 and Lys30. In each case, both the β³ homologue of the natural α residue and a cyclic β residue were evaluated. All α → β³ substitutions caused significant destabilization of the tertiary structure as measured by variable-temperature circular dichroism, although at some of these positions, replacing the β³ residue with a cyclic β residue led to improved stability. Atomic-resolution structures of four VHP analogues were obtained via quasiracemic crystallization. These findings contribute to a fundamental α/β-peptide knowledge-base by confirming that β³-amino acid residues can serve as effective structural mimics of homologous α-amino acid residues within a natural tertiary fold, which should support rational design of functional α/β analogues of natural poly-α-peptides

Evidence for Phenylalanine Zipper-Mediated Dimerization in the X‑ray Crystal Structure of a Magainin 2 Analogue

High-resolution structure elucidation has been challenging for the large group of host-defense peptides that form helices on or within membranes but do not manifest a strong folding propensity in aqueous solution. Here we report the crystal structure of an analogue of the widely studied host-defense peptide magainin 2. Magainin 2 (S8A, G13A, G18A) is a designed variant that displays enhanced antibacterial activity relative to the natural peptide. The crystal structure of magainin 2 (S8A, G13A, G18A), obtained for the racemic form, features a dimerization mode that has previously been proposed to play a role in the antibacterial activity of magainin 2 and related peptides

Economic Planning and Intersectoral Fiscal Policies

summary: this paper attacks the conventional wisdom that fiscal policies move an economy along a unique, downward-sloping, short-run phillips curve. in the context of a non-market-clearing model, it is shown that whenever demand-pull inflation and involuntary unemployment occur conjointly, (a) each sectoral government expenditure and each sectoral tax receipt is (in general) associated with a different phillips curve, (b) whereas some of these phillips curves may be downward-sloping, others maybe upward-sloping, and (c) sectoral fiscal policies which increase the budget deficit do not necessarily induce upward movements along their respective phillips curves and sectoral fiscal policies which reduce the budget deficit do not necessarily give rise to downward movements. the policy implication of this analysis is that the inflation-unemployment impact of aggregate government expenditures and aggregate tax receipts may be manipulated through their intersectoral breakdown.