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.

We review a recently developed ab initio multireference (MR)-density functional theory (DFT) approach based on the partially interacting reference systems. Instead of Kohn–Sham equations, we introduce the auxiliary CI equation with the effective DFT potential field. For practice, we classify electrons of the target system into valence electrons and other electrons. The former plays the quantum resonating feature of electronic structure of molecular species, while the latter affects the electronic properties via the effective correlation potential for the former electrons. The theoretical devices in our MR-DFT are introduced to avoid the double counting problem for any combination of a wavefunction and a correlation functional. Some numerical examples are presented.

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