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>3.0.co;2-o

Cited by 58 publications

(33 citation statements)

References 40 publications

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“…2, the ZnH 2 O 2+ -His and the ZnOH + -HisH + systems) averaged over many dynamical fluctuations of the enzyme–solvent system (for both His64 orientations) indicate that stable water clusters are indeed present for all end states examined. [14, 15, 29] It is through these and similar computer simulations that a molecular-scale interpretation of the role of the orientation of His64 and the intervening water clusters has been obtained.…”

Section: 0 Non-reactive Simulations Of His64 and The Active-site Wamentioning

confidence: 76%

Proton transport in carbonic anhydrase: Insights from molecular simulation

Maupin

Voth

2010

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Summary This article reviews the insights gained from molecular simulations of human carbonic anhydrase II (HCA II) utilizing non-reactive and reactive force fields. The simulations with a reactive force field explore protein transfer and transport via Grotthuss shuttling, while the non-reactive simulations probe the larger conformational dynamics that underpin the various contributions to the rate-limiting proton transfer event. Specific attention is given to the orientational stability of the His64 group and the characteristics of the active site water cluster, in an effort to determine both of their impact on the maximal catalytic rate. The explicit proton transfer and transport events are described by the multistate empirical valence bond (MS-EVB) method, as are alternative pathways for the excess proton charge defect to enter/leave the active site. The simulation results are interpreted in light of experimental results on the wild-type enzyme and various site-specific mutations of HCA II in order to better elucidate the key factors that contribute to its exceptional efficiency.

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Section: 0 Non-reactive Simulations Of His64 and The Active-site Wamentioning

confidence: 76%

Proton transport in carbonic anhydrase: Insights from molecular simulation

Maupin

Voth

2010

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…This model offers insights into how the substrate interacts with the active-site residues of the endopeptidase and which region of the active site is worth targeting to improve affinity and selectivity of a small-molecule inhibitor of the 5,9 Third, the four-ligand coordination of the zinc ion embedded in the active site of the endopeptidase can be computationally simulated with the cationic dummy atom (CaDA) approach [14][15][16][17][18] without resorting to the use of a covalent bond between zinc and its coordinate [19][20][21] or to semiempirical calculations. 22 This approach uses four identical dummy atoms tetrahedrically attached to the zinc ion and transfers all the atomic charge of the zinc divalent cation evenly to the four dummy atoms.…”

Section: Introductionmentioning

confidence: 99%

Serotype-selective, small-molecule inhibitors of the zinc endopeptidase of botulinum neurotoxin serotype A

Park

Sill

Makiyi

et al. 2006

Bioorganic & Medicinal Chemistry

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“…However, there is no evidence supporting the notion that the two conformers are in the kinetically stable state at a given pH. In addition, molecular dynamics simulations show that His 64 vibrates rather than swings; it could be flexible enough to find the optimum geometry between active site solvent molecules and the bulk solvent (17)(18)(19).…”

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confidence: 99%

Tautomerism of Histidine 64 Associated with Proton Transfer in Catalysis of Carbonic Anhydrase

Shimahara

Yoshida

Shibata

et al. 2007

Journal of Biological Chemistry

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. These reconstitute the water bridge. Based on these features, we suggest here a catalytic mechanism for hCAII: the tautomerization of His 64 can mediate the transfers of both protons and water molecules at a neutral pH with high efficiency, requiring no time-or energy-consuming processes.Carbonic anhydrase (CA) 2 (EC 4.2.1.1) is a ubiquitous enzyme that catalyzes the reversible hydration of carbon dioxide (1). Isozymes of carbonic anhydrase regulate or function in such diverse physiological processes as pH regulation, ion transport, water-electrolyte balance, bicarbonate secretion-absorption, bone resorption, maintenance of intraocular pressure, renal acidification, and brain development (2). Nonfunctioning CA is implicated in such diseases as osteopetrosis syndrome, glaucoma, respiratory acidosis, epilepsy, and Méni-ère syndrome. Diseases due to CA deficiency include those affecting bones, the brain, and the kidneys. Consequently determining the detailed structure/function relationships or mechanisms responsible for its catalytic properties is mandatory for developing inhibitors or replacement therapies.CA is present in at least three gene families (␣, ␤, and ␥), which has made it a popular model for the study of the evolution of gene families and protein folding, and for transgenic and gene target studies (2). Among the three families, the ␣ family is the best characterized, with 11 known isozymes identified in mammals. Earnhardt and co-workers have summarized maximal k cat and k cat /K m values for CO 2 hydration by isozyme I-VII (3). The human isozyme II (hCAII) has a remarkably high turnover rate or catalytic efficiency (k cat /K m ϭ 1.5 ϫ 10 8 M Ϫ1 s Ϫ1 ) that is very close to the frequency with which the enzyme and substrate molecules collide with each other in solution.It is widely accepted that the hydration of CO 2 catalyzed by hCAII proceeds through several chemical steps as shown in Scheme 1 (1, 4, 5): the direct nucleophilic attack of the zinc-bound hydroxide ion on the carbonyl carbon of substrate CO 2 (structures 1-2), the formation of a zinc-bound bicarbonate intermediate (structures 2-3), the isomerization of the bicarbonate ion (structures 3-4), the exchange of the product bicarbonate ion with a H 2 O (structures 4 -5), and the regeneration of the zinc-bound hydroxide ion by the transfer of a proton to bulk solvent (structures 1-5). The proton transfer step (structures 1-5) consists of two substeps: 1) an intra-molecular transfer of protons to another residue in the enzyme and 2) a release of protons to the outside of the enzyme with the aid of a base. The intra-molecular proton transfer is the rate-limiting step of the maximal turnover rate (10 6 s Ϫ1 ) at high concentrations of a base, whereas the proton release into the medium is rate-limiting at low buffer concentrations.

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

Cited by 58 publications

References 40 publications

Proton transport in carbonic anhydrase: Insights from molecular simulation

Proton transport in carbonic anhydrase: Insights from molecular simulation

Serotype-selective, small-molecule inhibitors of the zinc endopeptidase of botulinum neurotoxin serotype A

Tautomerism of Histidine 64 Associated with Proton Transfer in Catalysis of Carbonic Anhydrase

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