Intra- and Intermolecular Interaction Inducing Pyramidalization on Both Sides of a Proline Dipeptide during Isomerization: An Ab Initio QM/MM Molecular Dynamics Simulation Study in Explicit Water

Abstract

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.

Reoptimization of the AMBER Force Field Parameters for Peptide Bond (Omega) Torsions Using Accelerated Molecular Dynamics

“…However, in the transition state, the geometry of the prolyl nitrogen changes from trigonal planar to tetrahedral-like, which moves the nitrogen out-of-plane, giving rise to a pyramidal structure. As was done by Yonezawa et al, 48 we defined the degree of pyramidality as the volume of the tetrahedron formed by four atoms: prolyl nitrogen, carbonyl carbon of the preceding residue, C R , and C δ . We generated a two-dimensional free-energy landscape along the ω dihedral and pyramidality (Figure 3).…”

“…This is consistent with previous ab initio quantum mechanical MD studies. 30,48 Conclusion Generally, AMBER parameters for dihedrals are derived from fitting to relative energies of various ground state conformations obtained from quantum mechanical calculations on model compounds. In some cases, dihedral parameters are based on experimental data from thermodynamic and kinetic studies on the rotation of a specific torsional angle.…”

Degree of pyramidality governs the height and peak position of the free-energy-barrier for the cis–trans isomerization of N-Methylacetamide

“…It extended to 1.39 Å at 90°and 270°. The extension was clear evidence for the change in the character of the amide bond from an sp 2 to an sp 3 -hybridized electronic state, which reduces the rotational barrier of the isomerization to some extent [21]. It should be noted that the x dependence of the CAN bond length and that of the free energy landscape are well correlated.…”

“…doi:10.1016/j.cplett.2011.01.015 the system is sampled along an improper dihedral angle, C(@O)ANAHAC(AH3). Pyramidal conformations have been found both experimentally [16][17][18] and theoretically [19][20][21] to be associated with a lowered rotational barrier for the C(@O)AN bond. Even a small degree of pyramidal conformation has structural, spectroscopic, and chemical consequences.…”

Structure of the cyclic peptide [W8S]contryphan Vn: effect of the tryptophan/serine substitution on trans–cis proline isomerization

“…The study of the poly-l-proline revealed that the cis isomer of proline is conformationally compact and that, conversely, the trans isomer appears more stable in solvents such as water and TFE (Schimmel and Flory 1967;Deber et al 1970;Andreotti 2003). Kinetic studies performed by NMR (Buevich et al 2000) directly indicated that proline isomerizes by a single-step mechanism with an energy of 14-24 kcal mol −1 (Stein 1993;Fischer 2000) and that the interconversion is considered the rate limiting step in the folding of protein (Schmid and Baldwin 1978;Fischer 2000;Wedemeyer et al 2002) with a defined transition state (Yonezawa et al 2009). …”