Specific Reaction Parametrization of the AM1/d Hamiltonian for Phosphoryl Transfer Reactions:  H, O, and P Atoms

Nam, Kwangho; Cui, Qiang; Gao, Jiali; York, Darrin M.

doi:10.1021/ct6002466

Cited by 198 publications

(379 citation statements)

References 135 publications

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“…Specifically parameterized semi-empirical models have shown themselves to be invaluable at exploring different classes of highly specialized reactions. [8][9][10][11] a) Electronic mail: york@biomaps.rutgers.edu This work will outline a procedure for creating an Specific Reaction Parameterization (SRP) quantum model for chlorine within the Austin Model 1 (AM1) 12 Hamiltonian for the symmetric bimolecular nucleophilic reaction (S N 2) of a chlorine anion attacking methyl chloride in both the gas phase and in solution. Simple S N 2 reactions, such as the focus reaction of this study, are some of the most fundamental reactions in organic chemistry and have provided keen insights into gas phase reactivity and aqueous, solvation properties, reaction energetics, and kinetics over the past several decades.…”

Section: Introductionmentioning

confidence: 99%

Quantum mechanical study of solvent effects in a prototype SN2 reaction in solution: Cl− attack on CH3Cl

Kuechler

York

2014

The Journal of Chemical Physics

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The nucleophilic attack of a chloride ion on methyl chloride is an important prototype S N 2 reaction in organic chemistry that is known to be sensitive to the effects of the surrounding solvent. Herein, we develop a highly accurate Specific Reaction Parameter (SRP) model based on the Austin Model 1 Hamiltonian for chlorine to study the effects of solvation into an aqueous environment on the reaction mechanism. To accomplish this task, we apply high-level quantum mechanical calculations to study the reaction in the gas phase and combined quantum mechanical/molecular mechanical simulations with TIP3P and TIP4P-ew water models and the resulting free energy profiles are compared with those determined from simulations using other fast semi-empirical quantum models. Both gas phase and solution results with the SRP model agree very well with experiment and provide insight into the specific role of solvent on the reaction coordinate. Overall, the newly parameterized SRP Hamiltonian is able to reproduce both the gas phase and solution phase barriers, suggesting it is an accurate and robust model for simulations in the aqueous phase at greatly reduced computational cost relative to comparably accurate ab initio and density functional models. © 2014 AIP Publishing LLC. [http://dx

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Section: Introductionmentioning

confidence: 99%

Quantum mechanical study of solvent effects in a prototype SN2 reaction in solution: Cl− attack on CH3Cl

Kuechler

York

2014

The Journal of Chemical Physics

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“…62 Gln19 was treated quantum mechanically to explore its active role in mechanism II, since formation of a bond or charge transfer from OT atom of inhibitor must be considered as a possibility. His159 was treated quantum mechanically to explore mechanism III.…”

Section: Computational Modelmentioning

confidence: 99%

First Quantum Mechanics/Molecular Mechanics Studies of the Inhibition Mechanism of Cruzain by Peptidyl Halomethyl Ketones

2015

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Cruzain is a primary cysteine protease expressed by the protozoan parasite Trypanosoma cruzi during Chagas disease infection, and thus, the development of inhibitors of this protein is a promising target for designing an effective therapy against the disease. In this paper, the mechanism of inhibition of cruzain by two different irreversible peptidyl halomethyl ketones (PHK) inhibitors has been studied by means of hybrid quantum mechanics/molecular mechanics−molecular dynamics (MD) simulations to obtain a complete representation of the possible free energy reaction paths. These have been traced on free energy surfaces in terms of the potential of mean force computed at AM1d/MM and DFT/MM levels of theory. An analysis of the possible reaction mechanisms of the inhibition process has been performed showing that the nucleophilic attack of an active site cysteine, Cys25, on a carbon atom of the inhibitor and the cleavage of the halogen−carbon bond take place in a single step. PClK appears to be much more favorable than PFK from a kinetic point of view. This result would be in agreement with experimental studies in other papain-like enzymes. A deeper analysis of the results suggests that the origin of the differences between PClK and PFK can be the different stabilizing interactions established between the inhibitors and the residues of the active site of the protein. Any attempt to explore the viability of the inhibition process through a stepwise mechanism involving the formation of a thiohemiketal intermediate and a three-membered sulfonium intermediate has been unsuccessful. Nevertheless, a mechanism through a protonated thiohemiketal, with participation of His159 as a proton donor, appears to be feasible despite showing higher free energy barriers. Our results suggest that PClK can be used as a starting point to develop a proper inhibitor of cruzain.

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“…QM/MM calculations require of an efficient QM method, which explains the popularity of semiempirical Hamiltonians (often recalibrated to study reactions involving nucleic acids [17]). Recent successful example of semiempirical QM/MM calculation applied to nucleic acids include the study of the catalytic mechanism of the Human Flap Endonuclease (hFEN1) [18], th xc ll nt w k by Tuñ n's g u [19] on the mechanism of action of N6-adenosine methyltransferase, for which they described an ordered stepwise mechanism:…”

Section: Electronic Studiesmentioning

confidence: 99%

Multiscale simulation of DNA

Dans¹,

Walther

Gómez

et al. 2016

Current Opinion in Structural Biology

148

131

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DNA is not only among the most important molecules in life, but a meeting point for biology, physics and chemistry, being studied by numerous techniques. Theoretical methods can help in gaining a detailed understanding of DNA structure and function, but their practical use is hampered by the multiscale nature of this molecule. In this regard, the study of DNA covers a broad range of different topics, from sub-Angstrom details of the electronic distributions of nucleobases, to the mechanical properties of millimeter-long chromatin fibers. Some of the biological processes involving DNA occur in femtoseconds, while others require years. In this review, we describe the most recent theoretical methods that have been considered to study DNA, from the electron to the chromosome, enriching our knowledge on this fascinating molecule.

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Specific Reaction Parametrization of the AM1/d Hamiltonian for Phosphoryl Transfer Reactions: H, O, and P Atoms

Cited by 198 publications

References 135 publications

Quantum mechanical study of solvent effects in a prototype SN2 reaction in solution: Cl− attack on CH3Cl

Quantum mechanical study of solvent effects in a prototype SN2 reaction in solution: Cl− attack on CH3Cl

First Quantum Mechanics/Molecular Mechanics Studies of the Inhibition Mechanism of Cruzain by Peptidyl Halomethyl Ketones

Multiscale simulation of DNA

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