Stable Conformations of Tripeptides in Aqueous Solution Studied by UV Circular Dichroism Spectroscopy

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Abstract
Determination of the precise solution structure of peptides is of utmost importance to the understanding of protein folding and peptide drugs. Herein, we have measured the UV circular dichroism (UVCD) spectra of tri-alanine dissolved in D2O, H2O, and glycerol. The results clearly show the coexistence of a polyproline II or 31-helix and a somewhat disordered flat β-strand conformation, in complete agreement with recent predictions from spectroscopic data (Eker et al. J. Am. Chem. Soc.2002, 124, 14 330−14 341). A thermodynamic analysis revealed that enthalpic contributions of about 11 and 17 kJ/mol stabilize polyproline II in D2O and H2O, respectively, but at room temperature they are counterbalanced by entropic contributions, which clearly favor the more disordered β-strand conformation. It is hypothesized that this delicate balance is the reason for the variety of structural propensities of amino acid residues in the absence of nonlocal interactions. The isotope effect yielding a higher occupation of polyproline II in H2O with respect to D2O strongly suggests that a hydrogen-bonding network involving the peptide and water molecules in the hydration shell plays a major role in stabilizing this conformation. The equilibrium between polyproline II and β-strand is practically maintained in glycerol, which suggests that glycerol can substitute water as stabilizing solvent for the polyproline II conformation. We also measured the UVCD spectra of tri-valine and tri-lysine (both at acidic pD) in D2O and found them to adopt a flat β-strand and left-handed turn structure, respectively, in accordance with recent analyses of vibrational spectroscopy data. Generally, the present study adds substantial evidence to the notion that the so-called random coil state of peptides is much more structured than generally assumed.