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Analysis of the factors that stabilize a designed two-stranded antiparallel beta-sheet. Protein Sci 11:1492–1505

By Juan F. Espinosa, Faisal A. Syud, Samuel and H. Gellman


Autonomously folding �-hairpins (two-strand antiparallel �-sheets) have become increasingly valuable tools for probing the forces that control peptide and protein conformational preferences. We examine the effects of variations in sequence and solvent on the stability of a previously designed 12-residue peptide (1). This peptide adopts a �-hairpin conformation containing a two-residue loop (D-Pro-Gly) and a four-residue interstrand sidechain cluster that is observed in the natural protein GB1. We show that the conformational propensity of the loop segment plays an important role in �-hairpin stability by comparing 1 with D P → N mutant 2. In addition, we show that the sidechain cluster contributes both to conformational stability and to folding cooperativity by comparing 1 with mutant 3, in which two of the four cluster residues have been changed to serine. Thermodynamic analysis suggests that the high loop-forming propensity of the D PG segment decreases the entropic cost of �-hairpin formation relative to the more flexible NG segment, but that the conformational rigidity of D PG may prevent optimal contacts between the sidechains of the GB1-derived cluster. The enthalpic favorability of folding in these designed �-hairpins suggests that they are excellent scaffolds for studying the fundamental mechanisms by which amino acid sidechains interact with one another in folded proteins

Topics: �-sheet, �-hairpin, protein design, hydrophobic cluster Supplemental material, See
Year: 2002
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