Modeling the Ligand Effect on the Structure of CYP 450 Within the Density Functional Theory.

An improved understanding of the P450 structure is relevant to the development of biomimetic catalysts and inhibitors for controlled CH-bond activation, an outstanding challenge of synthetic chemistry. Motivated by the experimental findings of an unusually short Fe-S bond of 2.18 Šfor the wild-type (WT) OleT P450 decarboxylase relative to a cysteine pocket mutant form (A369P), a computational model that captures the effect of the thiolate axial ligand on the iron-sulfur distance is presented. With the computational efficiency and streamlined analysis in mind, this model combines a cluster representation of the enzyme─40-110 atoms, depending on the heme and ligand truncation level─with a density functional theory (DFT) description of the electronic structure (ES) and is calibrated against the experimental data. The optimized Fe-S distances show a difference of 0.25 Šbetween the low and high spin states, in agreement with the crystallographic structures of the OleT WT and mutant forms. We speculate that this difference is attributable to the packing of the ligand; the mutant is bulkier due to an alanine-to-proline replacement, meaning that it is excluded from the energetically favored low-spin minimum because of steric constraints. The presence of pure spin-state pairs and the intersection of the low/high spin states for the enzyme model is indicative of the limitations of single-reference ES methods in such systems and emphasizes the significance of using the proper state when modeling the hydrogen atom transfer (HAT) reaction catalyzed by OleT. At the same time, the correct characterization of both the short and long Fe-S bonds within a small DFT-based model of 42 atoms paves the way for quantum dynamics modeling of the HAT step, which initiates the OleT decarboxylation reaction.

Experimental and Theoretical Examination of the Kinetic Isotope Effect in Cytochrome P450 Decarboxylase OleT.

Using a combination of experimental studies, theory, simulation, and modeling, we investigate the hydrogen atom transfer (HAT) reaction by the high-valent ferryl cytochrome P450 (CYP) intermediate known as Compound I, a species that is central to innumerable and important detoxification and biosynthetic reactions. The P450 decarboxylase known as OleT converts fatty acids, a sustainable biological feedstock, into terminal alkenes and thus is of high interest as a potential means to produce fungible biofuels. Previous experimental work has established the intermediacy of Compound I in the C─C scission reaction catalyzed by OleT and an unprecedented ability to monitor the HAT process in the presence of bound fatty acid substrates. Here, we leverage the kinetic simplicity of the OleT system to measure the activation barriers for CYP HAT and the temperature dependence of the substrate 2H kinetic isotope effect. Notably, neither measurement has been previously accessible for a CYP to date. Theoretical analysis alludes to the significance of substrate fatty acid coordination for generating the hydrogen donor/acceptor configurations that are most conducive for HAT to occur. The analysis of the two-dimensional potential energy surface, based on multireference electronic wave functions, illustrates the uncoupled character of the hydrogen motion. Quantum dynamics calculations along the hydrogen reaction path demonstrate that hydrogen tunneling is essential to qualitatively capture the experimental isotope effect, its temperature dependence, and appropriate activation energies. Overall, a more fundamental understanding of the OleT reaction coordinate contributes to the development of biomimetic catalysts for controlled C─H bond activation, an outstanding current challenge for (bio)synthetic chemistry.

Multidimensional Tunneling Dynamics Employing Quantum-Trajectory Guided Adaptable Gaussian Bases.

An efficient basis representation of time-dependent wavefunctions is essential for theoretical studies of high-dimensional molecular systems exhibiting large-amplitude motion. For fully coupled anharmonic systems, the complexity of a general wavefunction scales exponentially with the system size; therefore, for practical reasons, it is desirable to adapt the basis to the time-dependent wavefunction at hand. Often times on this quest for a minimal basis representation, time-dependent Gaussians are employed, in part because of their localization in both configuration and momentum spaces and also because of their direct connection to classical and semiclassical dynamics, guiding the evolution of the basis function parameters. In this work, the quantum-trajectory guided adaptable Gaussian (QTAG) bases method [ J. Chem. Theory Comput. 2020, 16, 18-34] is generalized to include correlated, i.e., non-factorizable, basis functions, and the performance of the QTAG dynamics is assessed on benchmark system/bath tunneling models of up to 20 dimensions. For the popular choice of initial conditions describing tunneling between the reactant/product wells, the minimal "semiclassical" description of the bath modes using essentially a single multidimensional basis function combined with the multi-Gaussian representation of the tunneling mode is shown to capture the dominant features of dynamics in a highly efficient manner.

Quantum Dynamics with the Quantum Trajectory-Guided Adaptable Gaussian Bases.

The computational cost of describing a general quantum system fully coupled by anharmonic interactions scales exponentially with the system size. Thus, an efficient basis representation of wave functions is essential, and when it comes to the large-amplitude motion of high-dimensional systems, the dynamic bases of Gaussian functions are often employed. The time dependence of such bases is determined from the variational principle or from classical dynamics; the former is challenging in implementation due to singular matrices, while the latter may not cover the configuration space relevant to quantum dynamics. Here we describe a method using Quantum Trajectory-guided Adaptable Gaussian (QTAG) bases "tuned"-including the basis position, phase, and width-to the wave function evolution, thanks to the continuity of the probability density in the course of the quantum trajectory dynamics. Thus, an efficient basis in configuration space is generated, bypassing the variational equations on the parameters of the Gaussians. We also propose a time propagator with basis transformation by projections which lends efficiency and stability to the QTAG dynamics, as demonstrated on standard tests and the ammonia inversion model.