The Absence of Favorable Aromatic Interactions between β-Sheet Peptides

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Abstract
This paper asks whether interactions between phenylalanine (Phe) residues of the non-hydrogen-bonded cross-strand pairs of antiparallel β-sheets are important and finds that they are not. Peptides 1a − d [o-BuO−C6H4CO−AA1−Orn(i-PrCO−Hao)−Phe−Ile−AA5−NHMe: 1a AA1, AA5 = Phe; 1b AA1, AA5 = Cha (cyclohexylalanine); 1c AA1 = Phe, AA5 = Cha; 1d AA1 = Cha, AA5 = Phe] provide a sensitive system for probing interactions between phenylalanine residues. These peptides form β-sheet homodimers in organic solvents. When the homodimers of different peptides are mixed, they equilibrate to form heterodimers, as well as homodimers. The position of the equilibrium reflects the propensity of the first (AA1) and fifth (AA5) amino acids to interact within the non-hydrogen-bonded cross-strand pairs of β-sheets. Mixing peptides 1a−d in all six possible binary combinations provides a measure of the relative propensities of Phe and Cha to pair. Analysis by 1H NMR spectroscopy of the equilibrium constants in CDCl3 solution reveals no significant preference for the formation of Phe−Phe pairs. The equilibria in all six experiments are essentially statistical (K ≈ 4), and no (<0.1 kcal/mol) preference is seen for any pairing combination. A survey of Phe−Phe pairs in the Interchain β-Sheet Database (http://www.igb.uci.edu/servers/icbs/) corroborates that little significant contact occurs between the aromatic rings in the non-hydrogen-bonded cross-strand pairs of antiparallel β-sheets at the interface between polypeptide chains. Even though contacts between aromatic rings are favorable when they are of suitable geometry, the energetic price of achieving suitable geometries appears to offset the energetic benefits of such contacts in the current model system, as well as in proteins.