The gas-phase dipeptide analogue acetyl-phenylalanyl-amide: a model for the study of side chain/backbone interactions in proteins.

The issue of the influence of the side chain/backbone interaction on the local conformational preferences of a phenylalanine residue in a peptide chain is addressed. A synergetic approach is used, which combines gas-phase UV spectroscopy as well as gas-phase IR/UV double-resonance experiments with DFT and post Hartree-Fock calculations. N-Acetyl-Phe-amide was chosen as a model system for which three different conformers were observed. The most stable conformer has been identified as an extended beta(L) conformation of the peptide backbone. It is stabilized by a weak but significant NH-pi interaction bridging the aromatic ring on the residue (i) with the NH group on residue (i+1), with the aromatic side chain being in an anti conformation. This stable conformation corresponds to the common NH(i+1)-aromatic(i) interaction encountered in proteins for the three aromatic residues (phenylalanine, tyrosine, and tryptophan), which illustrates the relevance of gas-phase investigations to structural biology issues. The two other less abundant conformers have been assigned to two gamma-folded backbone conformations that differ by the orientation of the side chain. In all cases, the IR data provided spectroscopic fingerprints of these interactions. Finally, the strong conformational dependence of the fluorescence yield found for N-acetyl-Phe-amide illustrates the role of the environment on the excited-state dynamics of these species, which is often exploited by biochemists to monitor protein structural changes from tryptophan lifetime measurements.

Structure, electronic circular dichroism and Raman optical activity in the gas phase and in solution: a computational and experimental investigation.

A computational (ab initio and molecular dynamics) and experimental exploration of the relative importance of molecular conformation and explicit solvent effects on the electronic circular dichroism (ECD) of chiral molecules, is presented. The exploration includes an assessment of the validity of angular correlation (sector) rules linking ECD to molecular conformation. It is based upon studies of 1-(R) phenylethanol (including its Raman optical activity spectrum), the corresponding 'benchmark' base, 1-(R)-phenylethylamine and its protonated cation; their hydrated clusters in the gas phase; and their non-polar and aqueous solutions. Emphasis is placed on the influence of specific, hydrogen bonded interactions with the aqueous solvent. The theoretical validity of the (otherwise empirical) sector rule in the neutral molecules and in their specifically hydrated clusters has been established--but with a reversal of the 'historical' sign convention. Protonation of the amine leads to a breakdown of the conventional sector rule but the change in its ECD intensity can still be related to the side chain dihedral angular dependence of its rotatory strength, computed ab initio for its explicitly hydrated clusters. Comparisons between ECD spectra measured in aqueous and in hydrocarbon solutions and the results of molecular dynamics calculations for aqueous solutions at 300 K, identify solvent induced structural change as the principal determinant of their relative ECD spectral intensities. Further links connecting the structures and conformations of chiral molecules and their explicitly solvated clusters in the gas phase, to their structures and conformational populations in solution can be expected through measurement, ab initio computation and analysis of their vibrational, ROA spectra.