Molecular modelling of two coordination states of Zn(II) ion at the active site of human carbonic anhydrase II

Paul, Tanmoy Kumar; Taraphder, Srabani

doi:10.1016/j.chemphys.2021.111281

Cited by 4 publications

(9 citation statements)

References 66 publications

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“…A reproduction of the experimental rate constant in QM-MM enhanced sampling simulations is hard and rarely attempted. Our earlier work ,,, and the results presented in this article demonstrate a comprehensive simulation method where we combine QM-MM MD, transition path sampling, and the Markov state model to derive the most probable mechanism, reaction coordinate, free energy profile, and rate constant by analyzing a transition path ensemble. A summary of the insight thus derived on the catalysis of HCA II is shown in Figure .…”

Section: Resultsmentioning

confidence: 91%

“…The reaction coordinate is a postprocessing outcome of transition path sampling simulations, and thus, we could experiment using the same set of transition paths on several practical quantities such as an optimum number of order parameters ( N tot ), the need to use mutually orthogonal order parameters, { Q i }’s, optimal length of transition paths, and the level of quantum mechanical model in the QM-MM MD and TPS simulations . For multistep processes, methods such as Deep-LDA may be used to improve upon the selection procedure of CVs further.…”

Section: Resultsmentioning

confidence: 99%

“…For each residues in QM layer, C α –C β bonds were cut, and the unsatisfied valencies were capped using link hydrogen atoms. The QM layer was treated using the SCC-DFTB method , with appropriate Slater–Koster parameters. , The applicability of the semiempirical SCC-DFTB method in modeling the proton transfer step has been described elsewhere Low layer (MM layer): This layer includes the rest of the enzyme and bulk water molecules.…”

Section: Methodsmentioning

confidence: 99%

“…In a recent study, a transient pentacoordination state of Zn(II) ion, E•Zn ••His-64, was found to trigger the deprotonation of Zn-wat, thereby initiating the intramolecular proton transfer process. 65 Accordingly, the rate-determining proton transfer step in HCA II is studied in this work starting from a solvated structure of the enzyme, E•Zn ••His-64. Using QM/MM MD simulation and TPS, an ensemble of unbiased transition paths was harvested.…”

Section: ■ Introductionmentioning

confidence: 99%

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Nonlinear Reaction Coordinate of an Enzyme Catalyzed Proton Transfer Reaction

Paul

Taraphder

2022

J. Phys. Chem. B

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We present an in-depth study on the theoretical calculation of an optimum reaction coordinate as a linear or nonlinear combination of important collective variables (CVs) sampled from an ensemble of reactive transition paths for an intramolecular proton transfer reaction catalyzed by the enzyme human carbonic anhydrase (HCA) II. The linear models are optimized by likelihood maximization for a given number of CVs. The nonlinear models are based on an artificial neural network with the same number of CVs and optimized by minimizing the root-mean-square error in comparison to a training set of committor estimators generated for the given transition. The nonlinear reaction coordinate thus obtained yields the free energy of activation and rate constant as 9.46 kcal mol–1 and 1.25 × 106 s–1, respectively. These estimates are found to be in quantitative agreement with the known experimental results. We have also used an extended autoencoder model to show that a similar analysis can be carried out using a single CV only. The resultant free energies and kinetics of the reaction slightly overestimate the experimental data. The implications of these results are discussed using a detailed microkinetic scheme of the proton transfer reaction catalyzed by HCA II.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Nonlinear Reaction Coordinate of an Enzyme Catalyzed Proton Transfer Reaction

Paul

Taraphder

2022

J. Phys. Chem. B

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“…In the absence of these dynamical changes around the active site, no proton transfer reaction is observed even if hydrogen-bonded pathways are formed by the active site water molecules. 21 It is important to note that all inferences presented above on the catalysis by HCA II have been derived by sampling an ensemble of fluctuating structures of the enzyme at a finite temperature. No molecular level study on the functional dynamics of HCA IX is available.…”

Section: Introductionmentioning

confidence: 99%

Structure and Dynamics of the Isozymes II and IX of Human Carbonic Anhydrase

2022

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Human carbonic anhydrases (HCAs) are responsible for the pH control and sensing in our body and constitute key components in the central pH paradigm connected to cancer therapeutics. However, little or no molecular level studies are available on the pH-dependent stability and functional dynamics of the known isozymes of HCA. The main objective of this Article is to report the first bench-marking study on the structure and dynamics of the two most efficient isozymes, HCA II and IX, at neutral pH using classical molecular dynamics (MD) and constant pH MD (CpHMD) simulations combined with umbrella sampling, transition path sampling, and Markov state models. Starting from the known crystal structures of HCA II and the monomeric catalytic domain of HCA IX (labeled as HCA IX-c), we have generated classical MD and CpHMD trajectories (of length 1 μs each). In all cases, the overall stability, RMSD, and secondary structure segments of the two isozymes are found to be quite similar. Functionally important dynamics of these two enzymes have been probed in terms of active site hydration, coordination of the Zn(II) ion to a transient excess water, and the formation of putative proton transfer paths. The most important difference between the two isozymes is observed for the side-chain fluctuations of His-64 that is expected to shuttle an excess proton out of the active site as a part of the rate-determining intramolecular proton transfer reaction. The relative stability of the stable inward and outward conformations of the His-64 side-chain and the underlying free energy surfaces are found to depend strongly on the isozyme. In each case, a lower free energy barrier is detected between predominantly inward conformations from predominantly outward ones when simulated under constant pH conditions. The kinetic rate constants of interconversion between different free energy basins are found to span 10 7 –10 8 s –1 with faster conformational transitions predicted at constant pH condition. The estimated rate constants and free energies are expected to validate if the fluctuation of the His-64 side-chain in HCA IX may have a significance similar to that known in the multistep catalytic cycle of HCA II.

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Structure and non-reactive dynamics of the dimeric catalytic domain of human carbonic anhydrase IX

Rai,

Taraphder

2024

Chemical Physics Impact

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Molecular modelling of two coordination states of Zn(II) ion at the active site of human carbonic anhydrase II

Cited by 4 publications

References 66 publications

Nonlinear Reaction Coordinate of an Enzyme Catalyzed Proton Transfer Reaction

Nonlinear Reaction Coordinate of an Enzyme Catalyzed Proton Transfer Reaction

Structure and Dynamics of the Isozymes II and IX of Human Carbonic Anhydrase

Structure and non-reactive dynamics of the dimeric catalytic domain of human carbonic anhydrase IX

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