Quantum mechanics/molecular mechanics dual Hamiltonian free energy perturbation.

The dual Hamiltonian free energy perturbation (DH-FEP) method is designed for accurate and efficient evaluation of the free energy profile of chemical reactions in quantum mechanical/molecular mechanical (QM/MM) calculations. In contrast to existing QM/MM FEP variants, the QM region is not kept frozen during sampling, but all degrees of freedom except for the reaction coordinate are sampled. In the DH-FEP scheme, the sampling is done by semiempirical QM/MM molecular dynamics (MD), while the perturbation energy differences are evaluated from high-level QM/MM single-point calculations at regular intervals, skipping a pre-defined number of MD sampling steps.

Interactions of aromatic radicals with water.

The interactions of the benzyl radical (1), the anilinyl radical (2), and the phenoxyl radical (3) with water are investigated using density functional theory (DFT). In addition, we report dispersion-corrected DFT-D molecular dynamics simulations on these three systems and a matrix isolation study on 1-water. The radicals 1-3 form an interesting series with the number of lone pairs increasing from none to two.

Long-Range Electrostatic Effects in QM/MM Studies of Enzymatic Reactions: Application of the Solvated Macromolecule Boundary Potential.

Long-range electrostatic interactions are important in simulations of enzymatic reactions. They can be divided into the effects due to bulk solvent and those due to the electrostatic potential of the outer macromolecule. We study and quantify the importance of these two effects for two test systems by application of the solvated macromolecule boundary potential (SMBP) [J.

Coupling and uncoupling mechanisms in the methoxythreonine mutant of cytochrome P450cam: a quantum mechanical/molecular mechanical study.

The Thr252 residue plays a vital role in the catalytic cycle of cytochrome P450cam during the formation of the active species (Compound I) from its precursor (Compound 0). We investigate the effect of replacing Thr252 by methoxythreonine (MeO-Thr) on this protonation reaction (coupling) and on the competing formation of the ferric resting state and H2O2 (uncoupling) by combined quantum mechanical/molecular mechanical (QM/MM) methods. For each reaction, two possible mechanisms are studied, and for each of these the residues Asp251 and Glu366 are considered as proton sources.

A General Boundary Potential for Hybrid QM/MM Simulations of Solvated Biomolecular Systems.

We present a general boundary potential for the efficient and accurate evaluation of electrostatic interactions in hybrid quantum mechanical/molecular mechanical (QM/MM) approaches called solvated macromolecule boundary potential (SMBP), which is designed for QM/MM calculations with any kind of QM method. The SMBP targets QM/MM single-point energy calculations and geometry optimizations. In the SMBP scheme, the outer solvent and macromolecule region is described by a boundary potential obtained with the use of Poisson-Boltzmann calculations (treating the bulk solvent as a dielectric continuum).

QM/MM study of the second proton transfer in the catalytic cycle of the D251N mutant of cytochrome P450cam.

Protonation of Compound 0 in the catalytic cycle of cytochrome P450cam may lead to the formation of either the reactive Compound I (coupling) or the ferric resting state (uncoupling). In this work, we investigate the effect of the D251N mutation on the coupling and uncoupling reaction by combined quantum mechanics/molecular mechanics (QM/MM) calculations. The mutated Asn251 residue has two possible orientations, i.

How is the reactivity of cytochrome P450cam affected by Thr252X mutation? A QM/MM study for X = serine, valine, alanine, glycine.

Proton transfer reactions play a vital role in the catalytic cycle of cytochrome P450cam and are responsible for the formation of the iron-oxo species called Compound I (Cpd I) that is supposed to be the active oxidant. Depending on the course of the proton transfer, protonation of the last observable intermediate (ferric hydroperoxo complex, Cpd 0) can lead to either the formation of Cpd I (coupling reaction) or the ferric resting state (uncoupling reaction). The ratio of these two processes is drastically affected by mutation of the Thr252 residue.

Efficiency and Accuracy of the Generalized Solvent Boundary Potential for Hybrid QM/MM Simulations: Implementation for Semiempirical Hamiltonians.

We report the implementation of the generalized solvent boundary potential (GSBP) [ Im , W. , Bernèche , S. , and Roux , B.

Semiempirical double-hybrid density functional with improved description of long-range correlation.

The recently proposed new family of "double-hybrid" density functionals [Grimme, S. J. Chem.