11 research outputs found
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 β<sup>3</sup> homologue of the natural α residue and a cyclic β residue
were evaluated. All α → β<sup>3</sup> substitutions
caused significant destabilization of the tertiary structure as measured
by variable-temperature circular dichroism, although at some of these
positions, replacing the β<sup>3</sup> 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 β<sup>3</sup>-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.