Structural features of linear (alpha Me)Val-based peptides in solution by photophysical and theoretical conformational studies

In continuation of our studies on the determination of the structural featu res of functionalized peptides in solution by combining time-resolved fluor escence data and molecular mechanics results, the conformational features o f a series of linear, L-(alpha Me)Val-based peptides have been investigated in methanol. These foldamers have the general formula F((alpha Me)Val](r)- T-[(alpha Me)Val](2)NHtBu, where (alpha Me)Val = C-alpha-methylvaline and r = 0-3, while F [ = fluroren-9-ylmethoxycarbonyl (Fmoc)] and T [ = 2,2,6,6- tetramethylpiperidine-1-oxyl-4-amino-carboxylic (Toac)] are a fluorophoric N-alpha-protecting group and a nitroxide-based rr-amino acid quencher. resp ectively. According to ir and CD spectra. the longest term of the series (r = 3) attains a 3(10)-helical structure, while the other peptides populate an intramolecularly H-bonded, 3(10)-helix-like conformation affected by dyn amic helical distortions. which are enhanced by the shortness of the backbo ne chain. Such distortions are reflected in both the energy of the stretchi ng mode and the molar extinction coefficient of the H-bonded N-H groups. th e former being higher and the latter smaller than those of a stable 3(10)-h elix. Steady-state and time-resolved fluorescence measurements in methanol show a strong quenching of Fmoc by the Tone residue, located at different h elix positions. depending on the r value. Comparison of quenching efficienc ies tmd lifetime preexponents with those theoretically obtained from the de epest energy minimum conformers, assuming a Forster mechanism, is satisfact ory. The computed structures exhibit re rather compact arrangement. which a ccounts for the few sterically favored conformations for each peptide, in f ull agreement with the time-resolved fluorescence data. Orientational effec ts between the probes must be taken into account for a correct interpretati on of the fluorescence decay results. implying that interconversion among c onformational substates involving the probes is slower than the energy tran sfer rate. (C) 2001 John Wiley & Sons, Inc.