Hybrid Quantum and Molecular Mechanical Simulations:  An Alternative Avenue to Solvent Effects in Organic Chemistry

Gao, Jiali

doi:10.1021/ar950140r

Cited by 535 publications

(473 citation statements)

References 88 publications

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“…We can use the standard FEP equation (3) where β=1/(k B T); k B is the Boltzmann constant and T is the absolute temperature. The <> Ek stands for the average obtained during the propagation of the configurations using the potential of E k .…”

Section: Methodsmentioning

confidence: 99%

Accelerating QM/MM Free Energy Calculations: Representing the Surroundings by an Updated Mean Charge Distribution

et al. 2008

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Reliable studies of enzymatic reactions by combined quantum mechanical /molecular mechanics (QM(ai)/MM) approaches, with an ab initio description of the quantum region, presents a major challenge to computational chemists. The main problem is the need for very large computer time to evaluate the QM energy, which in turn makes it extremely challenging to perform proper configurational sampling. One of the most obvious options for accelerating QM/MM simulations is the use of an average solvent potential. In fact the idea of using an average solvent potential is rather obvious and has implicitly been used in Langevin dipole / QM calculations. However, in the case of explicit solvent models the practical implementations are more challenging and the accuracy of the averaging approach has not been validated. The present study introduces the average effect of the fluctuating solvent charges by using equivalent charge distributions, which are updated every m steps. Several models are evaluated in terms of the resulting accuracy and efficiency. The most effective model divides the system into an inner region with N explicit solvent atoms and an external region with two effective charges. Different models are considered in terms of the division of the solvent system and the update frequency. Another key element of our approach is the use of the free energy perturbation (FEP) and/or linear response approximation (LRA) treatments that guarantees the evaluation of the rigorous solvation free energy. Special attention is paid to the convergence of the calculated solvation free energies and the corresponding solute polarization. The performance of the method is examined by evaluating the solvation of a water molecule and a formate ion in water and also the dipole moment of water in water solution. Remarkably, it is found that different averaging procedures eventually converge to the same value but some protocols provide optimal ways of obtaining the final QM(ai)/MM converged results. The current method can provide computational time saving of 1000 for properly converging simulations relative to calculations that evaluate the QM(ai)/MM energy every time step. A specialized version of our approach that starts with a classical FEP charging and then evaluates the free energy of moving from the classical potential to the QM/ MM potential appears to be particularly effective. This approach should provide a very powerful tool for QM(ai)/MM evaluation of solvation free energies in aqueous solutions and proteins.

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Section: Methodsmentioning

confidence: 99%

Accelerating QM/MM Free Energy Calculations: Representing the Surroundings by an Updated Mean Charge Distribution

et al. 2008

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“…To this end, we have carried out statistical mechanical Monte Carlo and molecular dynamics simulations of the decarboxylation reaction of orotidylate in water and in the enzyme environment. The computational approach features a combined quantum mechanical and molecular mechanical (QM͞ MM) technique in which part of the substrate, the orotate group in the active site, is treated quantum mechanically and the surrounding solvent-enzyme system is approximated classically by the CHARMM22 force field (23,(26)(27)(28)(29). Because the electronic structure of the substrate is determined through Hartree-Fock molecular orbital calculations in the presence of the solvent- enzyme electric field throughout the fluid simulations, the enzyme action on the chemical reactivity in the bond dissociation process can be adequately investigated (29).…”

Section: Methodsmentioning

confidence: 99%

Electrostatic stress in catalysis: Structure and mechanism of the enzyme orotidine monophosphate decarboxylase

Gao

et al. 2000

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

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Orotidine 5 -monophosphate decarboxylase catalyzes the conversion of orotidine 5 -monophosphate to uridine 5 -monophosphate, the last step in biosynthesis of pyrimidine nucleotides. As part of a Structural Genomics Initiative, the crystal structures of the ligand-free and the6-azauridine 5 -monophosphate-complexed forms have been determined at 1.8 and 1.5 Å, respectively. The protein assumes a TIM-barrel fold with one side of the barrel closed off and the other side binding the inhibitor. A unique array of alternating charges (Lys-Asp-Lys-Asp) in the active site prompted us to apply quantum mechanical and molecular dynamics calculations to analyze the relative contributions of ground state destabilization and transition state stabilization to catalysis. The remarkable catalytic power of orotidine 5 -monophosphate decarboxylase is almost exclusively achieved via destabilization of the reactive part of the substrate, which is compensated for by strong binding of the phosphate and ribose groups. The computational results are consistent with a catalytic mechanism that is characterized by Jencks's Circe effect.O rotidine 5Ј-monophosphate decarboxylase (ODCase) (EC 4.1.1.23) formally catalyzes the exchange of CO 2 for a proton at the C 6 position to form uridine 5Ј-monophosphate (UMP) (1). The intermediate implied by this description consists of a C 6 -carbanion, the conjugate base of the UMP carbon acid. The ODCase reaction is unique in biological decarboxylation reactions in that the carbanion intermediate is not stabilized by conjugation interactions and, thus, the reaction rate is exceptionally slow in aqueous solution (2). The remarkable catalytic power of ODCase, which accelerates the reaction by 17 orders of magnitude over the aqueous process, has fascinated chemists and biochemists alike, leading to a number of proposals of mechanisms with novel features (3-7). However, as more results accumulated for this class of enzymes, possibilities for the mechanism became increasingly limited as cofactors and catalytic groups continued to be excluded from consideration (8-10). The high-resolution x-ray structure of ODCase from Methanobacterium thermoautotrophicum reveals that the mechanism is almost fully characterized by the formal description, along with electrostatic features of the enzyme's active site that provide selective destabilization of the orotidine group. In what follows, we report the results from a joint experimental and theoretical investigation, providing a mechanism that involves significant ground state destabilization effects in enzyme catalysis (11).The key to ODCase's catalytic power is its ability to utilize a phenomenon, which we classify as electrostatic stress [following Fersht's description of ''stress'' in catalysis (12)]. Although binding of the orotidine 5Ј-monophosphate (OMP) results in significant stabilizing interactions with the phosphate and ribose in the active site as revealed by the x-ray structural analysis, electrostatic interactions between the orotate group and ODCase is strongl...

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“…10 The analysis of enzyme- The aim of this work is to understand the molecular mechanism by which such molecules inhibit the catalytic activity of its target enzyme, which will be useful for designing potent inhibitors of O-GlcNAcase. Recently, we have successfully used molecular dynamics (MD) simulations, using a combined quantum mechanical/molecular mechanical (QM/MM) approach, [13][14][15] to study the relationship between protein-ligand interaction potential energies and HIV-1 IN inhibitor activity. 12 In the present work, electrostatic binding free energy of CpGH84H complexed with both PUGNAc and NAG-thiazoline have been computed.…”

Section: Inhibitors Of O-glcnacasementioning

confidence: 99%

A Quantum Mechanics/Molecular Mechanics Study of the Protein−Ligand Interaction of Two Potent Inhibitors of Human O-GlcNAcase: PUGNAc and NAG-Thiazoline

et al. 2008

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Hybrid Quantum and Molecular Mechanical Simulations: An Alternative Avenue to Solvent Effects in Organic Chemistry

Cited by 535 publications

References 88 publications

Accelerating QM/MM Free Energy Calculations: Representing the Surroundings by an Updated Mean Charge Distribution

Accelerating QM/MM Free Energy Calculations: Representing the Surroundings by an Updated Mean Charge Distribution

Electrostatic stress in catalysis: Structure and mechanism of the enzyme orotidine monophosphate decarboxylase

A Quantum Mechanics/Molecular Mechanics Study of the Protein−Ligand Interaction of Two Potent Inhibitors of Human O-GlcNAcase: PUGNAc and NAG-Thiazoline

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