The cis-trans isomerization of the peptide bond preceding a proline plays important roles in protein folding and biological function. Although many experimental and theoretical studies have been done, the mechanism has not yet been clearly elucidated. We studied the cis-trans isomerization of the proline dipeptide (Ace-Pro-NMe) in explicit water by molecular dynamics simulations using a combined potential derived from ab initio quantum mechanics and empirical molecular mechanics. We obtained the free energy landscape during the isomerization by using the umbrella sampling method. The free energy landscape is in good accordance with previous experimental and theoretical values. We observed that in the middle of the isomerization, the prolyl nitrogen transiently takes pyramidal conformations in two polarized directions and that, simultaneously, the prolyl C-N bond extends. We show that these geometrical changes cooperatively transform the prolyl nitrogen from a sp(2)-hybridized electronic state into a sp(3)-hybridized one, and thus realize a transition state that reduces the rotational barriers separating the cis- and trans-states. We also found that the hydration of the prolyl nitrogen stabilizes the negative pyramidal conformation, while an intramolecular interaction mainly stabilizes the positive one. Fluctuations in the polarity and magnitude of the pyramidal conformation during the isomerization are interpreted as a competition between the hydrogen-bonding partners for the prolyl nitrogen between different sides of the pyrrolidine ring.

The uniqueness of trehalose as a stress protectant may exist in its potential amphiphilic character capable of interacting with both hydrophilic and hydrophobic partners in aqueous solution. To address this issue, we here investigated the interaction between trehalose and aromatic compounds. NMR measurements, including (1)H-(1)H NOESY spectra, provide direct evidence for the formation of stable intermolecular complexes of trehalose with benzene (or p-cresol) in aqueous solution. In addition, corresponding theoretical evidence is provided by calculating the potential mean force as a function of the distance between trehalose and benzene. In the energy minimum structure, the benzene molecule is located only around the hydrophobic side of trehalose where the first hydration shell is not formed. Therefore, it can be concluded that benzene binds to trehalose in a fashion in which dehydration penalty is minimized. Finally, we discuss the possible biological roles of the trehalose-benzene interaction discovered here.

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