Molecular mechanics with proton transfer

The correlation of log kobs with H or J for the isotopic exchange of molecular hydrogen (Symons and Buncel, 1973) illustrates the difficulties that can arise in such procedures. The relevant plots, shown in Fig. 11, do not readily distinguish between the mechanism involving proton transfer (Wilmarth, 1953) and that in which an addition complex is formed (Ritchie and King, 1968). 

The solvated proton is not a point charge it exists in water in two solvated states of H30 aq and H502 aq and the location of the positive charge is smeared over the complex, as determined by quantum mechanical calculations. Any attempt to predict the location of a proton with 1A resolution is an overldir. With the present advances in structural biology, ultra-fast kinetic measurements and computational capabilities, the understanding of the mechanism of proton transfer at the interface should be based on experimental measurements capable of observing molecular events at a real time [2], coupled with an analysis that matches the molecular details of the reaction space. 

The initial geometry for formamide was set to the enol form as in Fig. 7.10. The atoms O, C, and N make a molecular plane, and the bridging water molecule is also placed initially so as to lie in that plane. In what follows, we refer to the molecular orbitals approximately lying on the plane and to those approximately perpendicular to the plane as a and tt orbitals, respectively. Likewise, using only tt orbitals in 7(r,f) and Bab (r.f)) we estimate the tt electron density and tt bond-order, respectively. Similarly, the a electron density and a bond-order are made available. This distinction between the a and tt subspaces is just a matter of convenience, and of course they are not physical observables individually, since Cs symmetry is not imposed on the molecular system. On the contrary, all the vibrational modes are active in the present SET calculations. Since the aim of this study is not to estimate the reaction probability but the mechanism of the electron dynamics associated with proton transfer, we chose somewhat artificial initial conditions of nuclear motion to sample as many paths achieving proton transfer as possible. 

Our theoretical investigation regarding the understanding of the conversion of iminium into enamine in the framework of a proline-catalyzed aldol reaction emphasizes that the reactive force field (FF), ReaxFF, used in combination with molecular dynamics (MD) simulations is a relevant method to investigate the mechanism of proton transfers in iminium-enamine conversions. This approach should be extended to model other steps of proline-catalyzed... 

To better understand the catalytic mechanism of DHFR and to use this information for the design of potent DHFR-specific inhibitors, we evaluated the proton and hydride transfers using an integrated ab initio Quantum Mechanics/Molecular Mechanics (QM/MM) approach in combination with FEP technology. The combinatorial application of these methods enabled us to propose a precise path along which the proton and hydride ion are transferred and to address the key structural and energetic changes associated with catalysis. 

A more recent view of proton transport is that of Kreuer, who, compared with the Zundel-based view, describes the process on different structural scales within phase separated morphologies. The smallest scale is molecular, which involves intermolecular proton transfer and the breaking and re-forming of hydrogen bonds. When the water content becomes low, the relative population of hydrogen bonds decreases so that proton conductance diminishes in a way that the elementary mechanism becomes that of the diffusion of hydrated protons, the so-called vehicle mechanism . 

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