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WIREs Comput Mol Sci
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Quantum and molecular mechanical Monte Carlo techniques for modeling condensed‐phase reactions

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A recent review (Acevedo O, Jorgensen WL. Advances in quantum and molecular mechanical (QM/MM) simulations for organic and enzymatic reactions. Acc Chem Res 2010, 43:142–151) examined our use and development of a combined quantum and molecular mechanical (QM/MM) technique for modeling organic and enzymatic reactions. Advances included the pairwise‐distance‐directed Gaussian (PDDG)/PM3 semiempirical QM (SQM) method, computation of multidimensional potentials of mean force (PMF), incorporation of on‐the‐fly QM in Monte Carlo simulations, and a polynomial quadrature method for rapidly treating proton‐transfer reactions. This article serves as a follow‐up on our progress. Highlights include new reactions, alternative SQM methods, a polarizable OPLS force field, and novel solvent environments, e.g., ‘on water’ and room temperature ionic liquids. The methodology is strikingly accurate across a wide range of condensed‐phase and antibody‐catalyzed reactions including substitution, decarboxylation, elimination, isomerization, and pericyclic classes. Comparisons are made to systems treated with continuum‐based solvents and ab initio or density functional theory (DFT) methods. Overall, the QM/MM methodology provides detailed characterization of reaction paths, proper configurational sampling, several advantages over implicit solvent models, and a reasonable computational cost. WIREs Comput Mol Sci 2014, 4:422–435. This article is categorized under: Electronic Structure Theory > Combined QM/MM Methods
Thermodynamic cycle for mutation of A to B in two solvents.
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Computed free energies (kcal/mol) for competitive proton abstraction pathways toward dienol intermediate formation; R = phenyl‐NHCOCH3. (Reproduced with permission from Ref . Copyright 2009, American Chemical Society)
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Free‐energy profile (kcal/mol) for the Kemp elimination of 5‐nitro‐benzisoxazole in antibody 4B2. The reaction coordinate for the proton transfer is OHCH with OH + CH = 2.85 Å. Maximum free‐energy values truncated to 30 kcal/mol for clarity. (Reproduced with permission from Ref . Copyright 2009, American Chemical Society)
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Antibody 4B2 catalyzed (a) Kemp elimination of 5‐nitro‐benzisoxazole and (b) allylic rearrangement of α‐cyclopent‐1‐en‐1‐yl‐p‐acetamidophenone (R = NHCOCH3) via a dienol or dienolate intermediate.
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Illustration of the ‘on water’ allyl p‐tolyl ether transition structure from the QM/MM/MC Claisen rearrangement calculations. (Reproduced with permission from Ref . Copyright 2010, American Chemical Society)
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Claisen rearrangement of (a) allyl p‐R‐phenyl ethers, R = CH3, Br, and OCH3 and (b) allyl naphthyl ether; and (c) the Diels‐Alder reaction between cyclopentadiene and 1,4‐naphthoquinone, methyl vinyl ketone, and acrylonitrile.
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Illustration of the encapsulation of the β‐elimination solute with piperidine transition state (given as a CPK space‐filling model) by nearby ions from [BMIM][BF4] (shown as sticks).
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β‐Elimination reaction of 1,1,1‐tribromo‐2,2‐bis(3,4‐dimethoxyphenyl)ethane.
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Reaction coordinates, RNH–RCH and RNO, used to locate stationary points from free‐energy maps obtained via PMF simulations for the Kemp elimination of benzisoxazole using piperidine. Illustrated structure corresponds to the transition state computed from QM/MM calculations.
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Henry reaction between formaldehyde and nitromethane and between benzaldehyde and nitropropane.
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Menshutkin reaction between triethylamine and ethyl iodide.
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Typical configuration for the transition structure for the Menshutkin reaction between triethylamine and ethyl iodide in water. Nearby hydrogen‐bonding water molecules are shown.
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