The covalent nature of interactions within various hydrogen bonded molecular aggregates has been characterized by the two entirely different computational methods: Bader analysis of the electron density and variation-perturbation partitioning of the intermolecular interaction energy. Analysis of 34 complexes representing different types of hydrogen bonds indicates that the proton-acceptor distance approximately 1.8 A and the ratio of delocalization and electrostatic terms approximately 0.45 constitutes approximately a borderline between covalent and noncovalent hydrogen bonds. The latter ratio could be used to characterize quantitatively the degree of the covalent nature of transition state interactions with active site residues, a quantity essential for an enzyme catalytic activity.

The results of a comprehensive study on the double-proton transfer in Adenine-Thymine (AT) and Guanine-Cytosine (GC) base pairs at room temperature in gas phase and with the inclusion of environmental effects are obtained. The double-proton-transfer process has been investigated in the AT and GC base pairs at the B3LYP/6-31G(d) and MP2/6-31G(d) levels of theory. It has been predicted that the hydrogen-bonded bases possess nonplanar geometries due to sp3 hybridization of nitrogen atoms and because of the soft intermolecular vibrations in the molecular complexes. An analysis of the energetic parameters of the local minima suggests that rare AT base pair conformation is not populated due to the shallowness of this minimum, which completely disappears from the Gibbs free energy surface. The stabilization of canonic or rare forms of the DNA bases by water molecules and metal cations has been predicted by calculating the optimal configuration of charges (using differential product/transition state stabilization approach) followed by calculations of the interactions between the base pair and a water/sodium cation.

Chorismate mutase is a key model system in the development of theories of enzyme catalysis. To analyze the physical nature of catalytic interactions within the enzyme active site and to estimate the stabilization of the transition state (TS) relative to the substrate (differential transition state stabilization, DTSS), we have carried out nonempirical variation-perturbation analysis of the electrostatic, exchange, delocalization, and correlation interactions of the enzyme-bound substrate and transition-state structures derived from ab initio QM/MM modeling of Bacillus subtilis chorismate mutase. Significant TS stabilization by approximately -23 kcal/mol [MP2/6-31G(d)] relative to the bound substrate is in agreement with that of previous QM/MM modeling and contrasts with suggestions that catalysis by this enzyme arises purely from conformational selection effects. The most important contributions to DTSS come from the residues, Arg90, Arg7, Glu78, a crystallographic water molecule, Arg116, and Arg63, and are dominated by electrostatic effects. Analysis of the differential electrostatic potential of the TS and substrate allows calculation of the catalytic field, predicting the optimal location of charged groups to achieve maximal DTSS. Comparison with the active site of the enzyme from those of several species shows that the positions of charged active site residues correspond closely to the optimal catalytic field, showing that the enzyme has evolved specifically to stabilize the TS relative to the substrate.

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To investigate fundamental features of enzyme catalysis, there is a need for high-level calculations capable of modelling crucial, unstable species such as transition states as they are formed within enzymes. We have modelled an important model enzyme reaction, the Claisen rearrangement of chorismate to prephenate in chorismate mutase, by combined ab initio quantum mechanics/molecular mechanics (QM/MM) methods. The best estimates of the potential energy barrier in the enzyme are 7.4-11.0 kcal mol(-1)(MP2/6-31+G(d)//6-31G(d)/CHARMM22) and 12.7-16.1 kcal mol(-1)(B3LYP/6-311+G(2d,p)//6-31G(d)/CHARMM22), comparable to the experimental estimate of Delta H(++)= 12.7 +/- 0.4 kcal mol(-1). The results provide unequivocal evidence of transition state (TS) stabilization by the enzyme, with contributions from residues Arg90, Arg7, and Arg63. Glu78 stabilizes the prephenate product (relative to substrate), and can also stabilize the TS. Examination of the same pathway in solution (with a variety of continuum models), at the same ab initio levels, allows comparison of the catalyzed and uncatalyzed reactions. Calculated barriers in solution are 28.0 kcal mol(-1)(MP2/6-31+G(d)/PCM) and 24.6 kcal mol(-1)(B3LYP/6-311+G(2d,p)/PCM), comparable to the experimental finding of Delta G(++)= 25.4 kcal mol(-1) and consistent with the experimentally-deduced 10(6)-fold rate acceleration by the enzyme. The substrate is found to be significantly distorted in the enzyme, adopting a structure closer to the transition state, although the degree of compression is less than predicted by lower-level calculations. This apparent substrate strain, or compression, is potentially also catalytically relevant. Solution calculations, however, suggest that the catalytic contribution of this compression may be relatively small. Consideration of the same reaction pathway in solution and in the enzyme, involving reaction from a 'near-attack conformer' of the substrate, indicates that adoption of this conformation is not in itself a major contribution to catalysis. Transition state stabilization (by electrostatic interactions, including hydrogen bonds) is found to be central to catalysis by the enzyme. Several hydrogen bonds are observed to shorten at the TS. The active site is clearly complementary to the transition state for the reaction, stabilizing it more than the substrate, so reducing the barrier to reaction.

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Ab initio calculations at the MP2/6-311++G(d,p) and MP2/aug-cc-pVDZ//MP2/aug-cc-pVTZ levels have been performed for the following complexes: H2OH+...HBeH, H2OH+...HBeBeH, H2OH+...HBeF, HClOH+...HBeH, Cl2OH+...HBeH, and Cl2OH+...HBeF. For all dimers considered, extremely short H...H intermolecular contacts (1.0-1.3 A) were obtained. These are the shortest intermolecular distances which have ever been reported, with binding energies within the range of 13.7-24.3 kcal/mol (MP2/aug-cc-pVDZ//MP2/aug-cc-pVTZ level). The interaction energies of the complexes analyzed were also extrapolated to the complete basis set (CBS) limit. To explain the nature of such strong interactions, the Bader theory was applied, and the characteristics of the bond critical points (BCPs) were analyzed. It was pointed out that for the major part of the H...H contacts considered here the Laplacian of the electron density at H...H BCP is negative indicating the partly covalent nature of such a connection. The term "covalent character of the hydrogen bond" used sometimes in recent studies is discussed. An analysis of the interaction energy components for dihydrogen bonded systems considered indicates that in contrast to conventional hydrogen bonded systems the attractive electrostatic term is outweighed by the repulsive exchange energy term and that the higher order delocalization energy term is the most important attractive term.

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