How Is the Active Site of Enolase Organized To Catalyze Two Different Reaction Steps?

Liu, Haiyan; Zhang, Yingkai; Yang, Weitao

doi:10.1021/ja9936619

Cited by 111 publications

(128 citation statements)

References 51 publications

(86 reference statements)

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“…The free energy gradient acting on QM atom i is computed as. (9) where the bracket represents ensemble averaging and the subscript r MM represents an ensemble of MM conformations. Therefore, the gradient of the PMF is in fact an ensemble average of the gradients of the QM atoms, which must be evaluated by sampling the phase space of the MM subsystem with the QM conformation frozen.…”

Section: Potential Of Mean Force Of the Qm Coordinatesmentioning

confidence: 99%

QM/MM Minimum Free-Energy Path: Methodology and Application to Triosephosphate Isomerase

Yang

2007

J. Chem. Theory Comput.

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139

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Structural and energetic changes are two important characteristic properties of a chemical reaction process. In the condensed phase, studying these two properties is very challenging because of the great computational cost associated with the quantum mechanical calculations and phase space sampling. Although the combined quantum mechanics/molecular mechanics (QM/MM) approach significantly reduces the amount of the quantum mechanical calculations and facilitates the simulation of solution phase and enzyme catalyzed reactions, the required quantum mechanical calculations remain quite expensive and extensive sampling can be achieved routinely only with semiempirical quantum mechanical methods. QM/MM simulations with ab initio QM methods, therefore, are often restricted to narrow regions of the potential energy surface such as the reactant, product and transition state, or the minimum energy path. Such ab initio QM/MM calculations have previously been performed with the QM/MM-Free Energy (QM/MM-FE) method of Zhang et al. 1 to generate the free energy profile along the reaction coordinate using free energy perturbation calculations at fixed structures of the QM subsystems. Results obtained with the QM/MM-FE method depend on the determination of the minimum energy reaction path, which is based on local conformations of the protein/solvent environment and can be difficult to obtain in practice. To overcome the difficulties associated with the QM/MM-FE method and to further enhance the sampling of the MM environment conformations, we develop here a new method to determine the QM/MM minimum free energy path (QM/MM-MFEP) for chemical reaction processes in solution and in enzymes. Within the QM/MM framework, we express the free energy of the system as a function of the QM conformation, thus leading to a simplified potential of mean force (PMF) description for the thermodynamics of the system. The free energy difference between two QM conformations is evaluated by the QM/MM free energy perturbation method. The free energy gradients with respect to the QM degrees of freedom are calculated from molecular dynamics simulations at given QM conformations. With the free energy and free energy gradients in hand, we further implement chain-of-conformation optimization algorithms in the search for the reaction path on the free energy surface without specifying a reaction coordinate. This method thus efficiently provides a unique minimum free energy path for solution and enzyme reactions, with structural and energetic properties being determined simultaneously. To further incorporate the dynamic contributions of the QM subsystem into the simulations, we develop the reaction path potential of Lu, et al. 2 for the minimum free energy path. The combination of the methods developed here presents a comprehensive and accurate treatment for the simulation of reaction processes in solution and in enzymes with ab initio QM/MM methods. The method has been demonstrated on the first step of the reaction of the enzyme triosephosphate isome...

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Section: Potential Of Mean Force Of the Qm Coordinatesmentioning

confidence: 99%

QM/MM Minimum Free-Energy Path: Methodology and Application to Triosephosphate Isomerase

Yang

2007

J. Chem. Theory Comput.

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139

198

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“…(Q ␤ is the partial charge of the MM atom; R ␣␤ is the distance between two atoms.) Such approximations have been successfully applied previously (26,27).…”

Section: Residue Contributions To Rate Of Misinsertion and Insertion mentioning

confidence: 99%

Incorrect nucleotide insertion at the active site of a G:A mismatch catalyzed by DNA polymerase β

Peng

Batra

Pedersen

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

100

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Based on a recent ternary complex crystal structure of human DNA polymerase ␤ with a G:A mismatch in the active site, we carried out a theoretical investigation of the catalytic mechanism of incorrect nucleotide incorporation using molecular dynamics simulation, quantum mechanics, combined quantum mechanics, and molecular mechanics methods. A two-stage mechanism is proposed with a nonreactive active-site structural rearrangement prechemistry step occurring before the nucleotidyl transfer reaction. The free energy required for formation of the prechemistry state is found to be the major factor contributing to the decrease in the rate of incorrect nucleotide incorporation compared with correct insertion and therefore to fidelity enhancement. Hence, the transition state and reaction barrier for phosphodiester bond formation after the prechemistry state are similar to that for correct insertion reaction. Key residues that provide electrostatic stabilization of the transition state are identified.combined quantum mechanics and molecular mechanics ͉ incorrect nucleotide incorporation ͉ nucleotidyl transfer ͉ two-stage mechanism I nsertion fidelity of DNA polymerases plays a central role in the replication and repair of DNA (1). DNA polymerase ␤ (pol ␤) is the simplest eukaryotic DNA polymerase. It catalyzes the template-directed nucleotidyl transfer reaction during the repair of ''simple'' base lesions with moderate fidelity, producing approximately one error per 3,000 nucleotides synthesized during base excision DNA repair (2). There is great interest in how pol ␤ achieves such fidelity without an intrinsic proofreading exonuclease. This interest is stimulated by a wealth of kinetic and site-directed mutagenesis studies available for pol ␤ (2, 3).A recent structural study of the precatalytic complex [pol ␤, DNA template, primer and a nonreactive deoxynucleoside triphosphate (dNTP) analogue, 2Ј-deoxy-adenosine-5Ј-(␣,␤)-methylene triphosphate (dAMPCPP)] provided for the first time a ternary complex structure with an active-site G:A mismatch (4). The two Mn 2ϩ ions in the active site were found to be octahedrally coordinated. The primer O3Ј group was found to be replaced by a water molecule, relative to its position in an earlier structure of a ternary complex with a matched (i.e., WatsonCrick) base pair (5).All families of DNA polymerases are believed to catalyze the nucleotidyl transfer reaction through a universal two-metal-ion mechanism (6). Reaction pathways for correct nucleotide incorporation have been extensively investigated by using various models. However, the reaction pathway for incorrect insertion is still unknown. Earlier studies had found that the rate of catalytic reaction for the correct base pair is a crucial factor in achieving high fidelity in DNA synthesis (7). The incorrect nucleotide insertion reaction catalyzed by DNA polymerases exhibiting modest to high fidelity is much slower than for the correct insertion (8, 9).A variety of computational techniques have been used in this study, including cl...

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“…The other type of QM/MM calculation [13,14,15,16,17,18,19,20,7] uses ab initio QM via wavefunction theory or density functional theory. DFT is the most popular approach because of the optimal balance of efficiency and accuracy [21,22,23].…”

Section: Introductionmentioning

confidence: 99%

“…Carry out a QM optimization with the MM ensemble fixed at where the object of minimization is the QM PMF (or QM free energy) in the n-th iteration given by a finite sum representation of free energy perturbation as (15) and the corresponding gradient with respect to the i-th QM coordinate is also given by the finite sum (16) where (17) which accounts for the fact that the samples were obtained from a fixed MD simulation of a reference state. c. Update the reference structure based on the minimized QM structure .…”

mentioning

confidence: 99%

Free Energies of Chemical Reactions in Solution and in Enzymes with Ab Initio Quantum Mechanics/Molecular Mechanics Methods

Yang

2008

Annu. Rev. Phys. Chem.

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417

401

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Combined QM/MM methods provide an accurate and efficient energetic description of complex chemical and biological systems, leading to significant advances in the understanding of chemical reactions in solution and in enzymes. Progress in QM/MM methodology and application will be reviewed, with a focus on ab initio QM based approaches. Ab initio QM/MM methods capitalize on the accuracy and reliability of the associated quantum mechanical approaches, however at a much higher computational cost compared with semiempirical quantum mechanical approaches. Thus reaction path and activation free energy calculations based on ab initio QM/MM methods encounter unique challenges in simulation timescales and phase space sampling. Recent developments overcoming these challenges and enabling accurate free energy determination for reaction processes in solution and enzymes will be featured in this review, along with applications.

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How Is the Active Site of Enolase Organized To Catalyze Two Different Reaction Steps?

Cited by 111 publications

References 51 publications

QM/MM Minimum Free-Energy Path: Methodology and Application to Triosephosphate Isomerase

QM/MM Minimum Free-Energy Path: Methodology and Application to Triosephosphate Isomerase

Incorrect nucleotide insertion at the active site of a G:A mismatch catalyzed by DNA polymerase β

Free Energies of Chemical Reactions in Solution and in Enzymes with Ab Initio Quantum Mechanics/Molecular Mechanics Methods

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