Ab initio calculations have been performed to probe possible proton-transfer pathways in carbonic anhydrase. It is found that the proton transfer in the dehydration direction involves an energy barrier of around 8−10 kcal/mol, which agrees well with experiment, while the proton-transfer barrier in the hydration (away from zinc) direction is sensitive to the histidine ligand bonding around the Zn ion. The water ligand dependence of the proton-transfer energy barrier reveals a requirement of certain hydrogen bond formation in the active site. Preliminary studies involving two and three proton transfers through hydrogen-bonded water chains show that the donor−acceptor distance and the water chain motion are crucial to the proton-transfer energetics. On the basis of these results, a picture of the proton-transfer energetics and mechanism is presented and the effect of the His-64 ligand on the process is discussed.

In this paper, the carbonic anhydrase II (CA II) enzyme active site is modeled using ab initio calculations and molecular dynamics simulations to examine a number of important issues for the enzyme function. It is found that the Zn2+ ion is dominantly tetrahedrally coordinated, which agrees with X-ray crystallographic studies. However, a transient five-fold coordination with an extra water molecule is also found. Studies of His64 conformations upon a change in the protonation states of the Zn-bound water and the His64 residue also confirm the results of an X-ray study which suggest that the His64 conformation is quite flexible. However, the degree of water solvation is found to affect this behavior. Water bridge formation between the Zn-bound water and the His64 residue was found to involve a free energy barrier of 2-3 kcal/mol and an average lifetime of several picoseconds, which supports the concept of a proton transfer mechanism through such a bridge. Mutations of various residues around the active site provide further insight into the corresponding experimental results and, in fact, suggest an important role for the solvent water molecules in the CA II catalytic mechanism.

The influence of nuclear quantum effects on the excess proton in water is examined through quantum dynamical computer simulations. Results are presented for the isotope effects on both the proton exchange process and the infrared absorption spectrum. A critical assessment of the accuracy of density-functional-theory-based molecular dynamics simulation methods for addressing this problem is also given.

In this paper, the carbonic anhydrase II (CA II) enzyme active site is modeled using ab initio calculations and molecular dynamics simulations to examine a number of important issues for the enzyme function. It is found that the Zn2+ ion is dominantly tetrahedrally coordinated, which agrees with X-ray crystallographic studies. However, a transient five-fold coordination with an extra water molecule is also found. Studies of His64 conformations upon a change in the protonation states of the Zn-bound water and the His64 residue also confirm the results of an X-ray study which suggest that the His64 conformation is quite flexible. However, the degree of water solvation is found to affect this behavior. Water bridge formation between the Zn-bound water and the His64 residue was found to involve a free energy barrier of 2-3 kcal/mol and an average lifetime of several picoseconds, which supports the concept of a proton transfer mechanism through such a bridge. Mutations of various residues around the active site provide further insight into the corresponding experimental results and, in fact, suggest an important role for the solvent water molecules in the CA II catalytic mechanism.

We have studied solvation of an ion in model polar clusters of Stockmayer (Lennard-Jones + point dipole) particles to test previous theories of cluster ion solvation, and to elucidate trends that may serve as a point of departure for analysis of more complex systems. We find that the pure solvent cluster is not isotropic, but has a well-defined pattern of orientational order which is converted to another distinct pattern by the ion. The extent to which the cluster is reordered depends upon the relative magnitude of ionic strength and solvent polarity. In many instances the two forms of order coexist with solvent shells far from the ion behaving as they did before inclusion of the ion, which shells close to the ion are reordered in a manner that best solvates the ion. The location of the ion in the cluster depends on relative ionic strength as well. The location changes from the surface to the center of the cluster in a gradual manner as the relative ionic strength increases. Qualitative agreement with dielectric continuum theory is found for large clusters. Deviations from dielectric continuum theory are found for small clusters, as expected, and compared to a previous theoretical prediction of those deviations.