Molecular dynamics simulations of human carbonic anhydrase II: Insight into experimental results and the role of solvation

Lu, Dongsheng; Voth, Gregory A.

doi:10.1002/(sici)1097-0134(19981001)33:1<119::aid-prot11>3.3.co;2-d

Cited by 31 publications

(71 citation statements)

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“…The second-round of equilibration and subsequent umbrella sampling production runs for HCA II used the newly constructed RESP charges (supporting information) and modified parm99 (44) parameters (supporting information). ( 20,40 ) In addition to these modified parameters it was determined during the second-round of equilibration that the distance between the zinc and the zinc bound water was shorter than x-ray and ONIOM values. This shortening of the bond was most likely due to the new charge distributions.…”

Section: Active Site Geometriesmentioning

confidence: 99%

Preferred Orientations of His64 in Human Carbonic Anhydrase II

2007

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Histidine at position 64 (His64) in human carbonic anhydrase II (HCA II) is believed to be the proton acceptor in the hydration direction and the proton donor in the dehydration direction for the rate-limiting proton transfer (PT) event. Although the biochemical effect of histidine at position 64 has been thoroughly investigated, the role of its orientation in the PT event is a topic of considerable debate. X-ray data of HCA II suggests that His64 can adopt either an "in" or "out" orientation. The "in" orientation is believed to be favored for the hydration direction PT event because the Ndelta of His64 is closer to the catalytic zinc. This orientation allows for smaller water bridges, which are postulated to be more conducive to PT. In the present work, classical molecular dynamics simulations have been conducted to elucidate the role that the His64 orientation may play in its ability to act as a proton donor/acceptor in HCA II. The free energy profile for the orientation of His64 suggests that the histidine will adopt an "in" orientation in the hydration direction, which brings Ndelta in close proximity to the catalytic zinc. When the histidine becomes protonated, it then rotates to an "out" orientation, creating a more favorable solvation environment for the protonated His64. In this "out" orientation, the imidazole ring releases the delta nitrogen's excess proton into the bulk environment. After the second PT event and when the zinc-bound water is regenerated, the His64 is again favored to reorient to the "in" orientation, completing the catalytic cycle.

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Section: Active Site Geometriesmentioning

confidence: 99%

Preferred Orientations of His64 in Human Carbonic Anhydrase II

2007

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“…Here we briefly compare QM/ MM-GSBP with more traditional QM/MM simulations using the stochastic boundary condition with different approximate treatments for electrostatics. 67,68 A more thorough analysis and comparison of QM/MM simulations using GSBP and other boundary conditions as well as previous theoretical studies [69][70][71][72] will be reported separately.…”

Section: Carbonic Anhydrase IImentioning

confidence: 99%

Reliable treatment of electrostatics in combined QM/MM simulation of macromolecules

Schaefer

Riccardi

Cui

2005

The Journal of Chemical Physics

133

206

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A robust approach for dealing with electrostatic interactions for spherical boundary conditions has been implemented in the QM/MM framework. The development was based on the generalized solvent boundary potential (GSBP) method proposed by Im et al. [J. Chem. Phys. 114, 2924 (2001)], and the specific implementation was applied to the self-consistent-charge density-functional tight-binding approach as the quantum mechanics (QM) level, although extension to other QM methods is straightforward. Compared to the popular stochastic boundary-condition scheme, the new protocol offers a balanced treatment between quantum mechanics/molecular mechanics (QM/MM) and MM/MM interactions; it also includes the effect of the bulk solvent and macromolecule atoms outside of the microscopic region at the Poisson-Boltzmann level. The new method was illustrated with application to the enzyme human carbonic anhydrase II and compared to stochastic boundary-condition simulations using different electrostatic treatments. The GSBP-based QM/MM simulations were most consistent with available experimental data, while conventional stochastic boundary simulations yielded various artifacts depending on different electrostatic models. The results highlight the importance of carefully treating electrostatics in QM/MM simulations of biomolecules and suggest that the commonly used truncation schemes should be avoided in QM/MM simulations, especially in simulations that involve extensive conformational samplings. The development of the GSBP-based QM/MM protocol has opened up the exciting possibility of studying chemical events in very complex biomolecular systems in a multiscale framework.

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“…The distance between the zinc-bound water and His 64 is about 8 Å in the x-ray structure, which led to the suggestion that PT has to be mediated by water molecules in the active site [90][91][92]. Although two-water molecules have been observed in the x-ray structures that connect the zinc-bound water and His 64 through hydrogen bonds, simulation studies with different potential functions [28,29,83] have shown that the water structure in the active site is rather dynamical and water bridges connecting the zinc site and His 64 typically include from two to four water molecules. The on-going debate [22,23,25,26,28,29] concerns whether formation of a specific type of water bridge contributes dominantly to the kinetic bottleneck of the PT and whether the PT proceeds through a concerted or step-wise mechanism [24][25][26][27]93].…”

Section: Proton Transfer In Carbonic Anhydrase IImentioning

confidence: 99%

Toward Theoretical Analyis of Long-Range Proton Transfer Kinetics in Biomolecular Pumps

et al. 2005

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Motivated by the long-term goal of theoretically analyzing long-range proton transfer (PT) kinetics in biomolecular pumps, researchers made a number of technical developments in the framework of quantum mechanics-molecular mechanics (QM/MM) simulations. A set of collective reaction coordinates is proposed for characterizing the progress of long-range proton transfers; unlike previous suggestions, the new coordinates can describe PT along highly nonlinear three-dimensional pathways. Calculations using a realistic model of carbonic anhydrase demonstrated that adiabatic mapping using these collective coordinates gives reliable energetics and critical geometrical parameters as compared to minimum energy path calculations, which suggests that the new coordinates can be effectively used as reaction coordinate in potential of mean force calculations for long-range PT in complex systems. In addition, the generalized solvent boundary potential was implemented in the QM/MM framework for rectangular geometries, which is useful for studying reactions in membrane systems. The resulting protocol was found to produce water structure in the interior of aquaporin consistent with previous studies including a much larger number of explicit solvent and lipid molecules. The effect of electrostatics for PT through a membrane protein was also illustrated with a simple model channel embedded in different dielectric continuum environments. The encouraging results observed so far suggest that robust theoretical analysis of long-range PT kinetics in biomolecular pumps can soon be realized in a QM/MM framework.

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Molecular dynamics simulations of human carbonic anhydrase II: Insight into experimental results and the role of solvation

Cited by 31 publications

References 0 publications

Preferred Orientations of His64 in Human Carbonic Anhydrase II

Preferred Orientations of His64 in Human Carbonic Anhydrase II

Reliable treatment of electrostatics in combined QM/MM simulation of macromolecules

Toward Theoretical Analyis of Long-Range Proton Transfer Kinetics in Biomolecular Pumps

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