Isolated Monohydrates of a Model Peptide Chain: Effect of a First Water Molecule on the Secondary Structure of a Capped Phenylalanine

Abstract

The formation of monohydrates of capped phenylalanine model peptides, CH(3)-CO-Phe-NH(2) and CH(3)-CO-Phe-NH-CH(3), in a supersonic expansion has been investigated using laser spectroscopy and quantum chemistry methods. Conformational distributions of the monohydrates have been revealed by IR/UV double-resonance spectroscopy and their structures assigned by comparison with DFT-D calculations. A careful analysis of the final hydrate distribution together with a detailed theoretical investigation of the potential energy surface of the monohydrates demonstrates that solvation occurs from the conformational distribution of the isolated peptide monomers. The distribution of the monohydrates appears to be strongly dependent on both the initial monomer conformation (extended or folded backbone) and the solvation site initially occupied by the water molecule. The solvation processes taking place during the cooling can be categorized as follows: (a) solvation without significant structural changes of the peptide, (b) solvation inducing significant distortions of the backbone but retaining the secondary structure, and (c) solvation triggering backbone isomerizations, leading to a modification of the peptide secondary structure. It is observed that solvation by a single water molecule can fold a β-strand into a γ-turn structure (type c) or induce a significant opening of a γ-turn characterized by an elongated C(7) hydrogen bond (type b). These structural changes can be considered as a first step toward the polyproline II condensed-phase structure, illustrating the role played by the very first water molecule in the solvation process.

Isolated Neutral Peptides

“…One of the most dramatic studies, carried out on a capped amino-acid solvated by one water molecule, documented the effect of microhydration and its dependence on the solvation site occupied by the water molecule for each conformation. It provided evidence of a complete conformational distribution reversal where a folded backbone form overcomes an extended structure as the most stable when solvated by a single water molecule [53]. The presence of this first molecule, which bridges the two ends of the protected peptide (Fig.…”

“…Errors of the order of a few kJ mol À1 for the 0 K enthalpy and up to 5 kJ mol À1 for the Gibbs energies can be anticipated on systems as large as dipeptides, including those where dispersion plays a decisive shaping role, as in aromatic-containing peptide chains [95,96,99,103,111,112,135,160]. Correlatively, the development of these functionals provides faster calculations, making possible the investigation of even larger systems [53,107,128,134,139].…”

“…Mode-dependent linear (ν th scaled ¼ a ν raw + b) scaling functions constitute the finest variation of this pragmatic approach. Particularly well-suited for systems with vibrational probes of different nature, it reached an unsurpassed precision in the 20 cm À1 range when applied to peptide hydrates in the amide A region [53,107] (Fig. 3a).…”

“…Early formation enables the complex to rearrange and find the most stable structures, whereas an aggregation in the late stages of the expansion favours the easiest way to assemble the partners from their own initial distribution. This kinetic trapping has been observed to play a predominant role by hampering a full exploration of peptide hydrates during the expansion [53]. In particular, it can explain that a few conformers, for which water needs energy to insert in an already formed H-bond between a donor and an acceptor site of the peptide, are not observed, despite their predicted low energy.…”

“…Theoretically predicted some time ago [196], experimental illustrations of these effects have been published only quite recently. Several groups have shown that peptides or related flexible molecules undergo a significant structural change upon solvation, as indicated by changes in their H-bonding network [53,55,102,129,136]. One of the most dramatic studies, carried out on a capped amino-acid solvated by one water molecule, documented the effect of microhydration and its dependence on the solvation site occupied by the water molecule for each conformation.…”