Proton Transfer in the Enzyme Carbonic Anhydrase:  An ab Initio Study

Abstract

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.

Monte Carlo simulations of proton pumps: On the working principles of the biological valve that controls proton pumping in cytochrome c oxidase

“…Such a structure-function correlation approach has recently been developed (12), but the absence of a proper simulation approach prevented its use in quantitative time-dependant studies. Apparently, although significant advances have been made in short time simulations of PTR in solutions and in biological systems (25)(26)(27), no method has been able to bridge the time gap and to simulate biological PTR in the long times that are typically involved in proton-pumping processes. This difficulty and other problems have so far prevented a faster progress in understanding PTR in COX and related systems.…”

Carbonic Anhydrase: New Insights for an Ancient Enzyme

“…Finally, ab initio studies of intramolecular proton transfer indicate that the donor-acceptor distance and the water chain motion are essential to the energetics (20).…”

Anomalous Acid-Base Equilibria in Biologically Relevant Water Nanopools

“…5) 17 but similar to that of an alcohol (ε = [30][31][32][33][34][35][36][37][38][39][40]. 18,19 On the other hand, biological processes often take place based on proton relay along a hydrogen (H)-bonded chain, [1][2][3][4][20][21][22][23][24] and the dynamics of biological proton relay is determined by the size, the structure, and the motion of a water cluster which is the prime agent in most of biological systems. 3,[13][14][15][24][25][26] Thus, for better understanding of cellular dynamics, it is necessary to investigate the properties of a biologically relevant water nanopool as a biomimetic system of water confined in a cell membrane.…”

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Water plays a crucial role in many principal biological phenomena such as enzymatic catalysis and proton pumping through a membrane protein channel.1-4 Moreover, in biological systems, water is usually contained in a small pocket of a membrane, 5-8 and such confined water, which is generally called a water nanopool, [8][9][10] shows peculiar properties differing considerably from the properties of bulk water.

8-16The confinement effect and the enclosing interfacial surfaces of waterpools are the main factors to determine the properties, such as polarity, viscosity, and H-bonding ability, of water nanopools.5-13 For example, the dielectric constant of a water nanopool has been reported to be much lower than that of bulk water (ε = 78.5)17 but similar to that of an alcohol (ε = 30-40).18,19 On the other hand, biological processes often take place based on proton relay along a hydrogen (H)-bonded chain, [1][2][3][4][20][21][22][23][24] and the dynamics of biological proton relay is determined by the size, the structure, and the motion of a water cluster which is the prime agent in most of biological systems. 3,[13][14][15][24][25][26] Thus, for better understanding of cellular dynamics, it is necessary to investigate the properties of a biologically relevant water nanopool as a biomimetic system of water confined in a cell membrane.

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