Interstrand Side Chain−Side Chain Interactions in a Designed β-Hairpin: Significance of Both Lateral and Diagonal Pairings

Publisher Website
Google Scholar
Abstract
The contributions of interstrand side chain−side chain contacts to β-sheet stability have been examined with an autonomously folding β-hairpin model system. RYVEVDPGOKILQ-NH2 (DP = d-proline, O = ornithine) has previously been shown to adopt a β-hairpin conformation in aqueous solution, with a two-residue loop at d-Pro-Gly. In the present study, side chains that display interstrand NOEs (Tyr-2, Lys-9, and Leu-11) are mutated to alanine or serine, and the conformational impact of the mutations is assessed. In the β-hairpin conformation Tyr-2 and Leu-11 are directly across from one another (non-hydrogen bonded pair). This “lateral” juxtaposition of two hydrophobic side chains appears to contribute to β-hairpin conformational stability, which is consistent with results from other β-sheet model studies and with statistical analyses of interstrand residue contacts in protein crystal structures. Interaction between the side chains of Tyr-2 and Lys-9 also stabilizes the β-hairpin conformation. Tyr-2/Lys-9 is a “diagonal” interstrand juxtaposition because these residues are not directly across from one another in terms of the hydrogen bonding registry between the strands. This diagonal interaction arises from the right-handed twist that is commonly observed among β-sheets. Evidence of diagonal side chain−side chain contacts has been observed in other autonomously folding β-sheet model systems, but we are not aware of other efforts to determine whether a diagonal interaction contributes to β-sheet stability.