Competing interactions contributing to α‐helical stability in aqueous solution

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Abstract
The stability of a 15-residue peptide has been investigated using CD spectroscopy and molecular simulation techniques. The sequence of the peptide was designed to include key features that are known to stabilize α-helices, including ion pairs, helix dipole capping, peptide bond capping, and aromatic interactions. The degree of helicity has been determined experimentally by CD in three solvents (aqueous buffer, methanol, and trifluoroethanol) and at two temperatures. Simulations of the peptide in the aqueous system have been performed over 500 ps at the same two temperatures using a fully explicit solvent model. Consistent with the CD data, the degree of helicity is decreased at the higher temperature. Our analysis of the simulation results has focused on competition between different side-chain/side-chain and side-chain/main-chain interactions, which can, in principle, stabilize the helix. The unfolding in aqueous solution occurs at the amino terminus because the side-chain interactions are insufficient to stabilize both the helix dipole and the peptide hydrogen bonds. Loss of capping of the peptide backbone leads to water insertion within the first peptide hydrogen bond and hence unfolding. In contrast, the carboxy terminus of the α-helix is stable in both simulations because the C-terminal lysine residue stabilizes the helix dipole, but at the expense of an ion pair.