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Xanthine oxidase-product complexes probe the importance of substrate/product orientation along the reaction coordinate.

ABSTRACT: A combination of reaction coordinate computations, resonance Raman spectroscopy, spectroscopic computations, and hydrogen bonding investigations have been used to understand the importance of substrate orientation along the xanthine oxidase reaction coordinate. Specifically, 4-thiolumazine and 2,4-dithiolumazine have been used as reducing substrates for xanthine oxidase to form stable enzyme-product charge transfer complexes suitable for spectroscopic study. Laser excitation into the near-infrared molybdenum-to-product charge transfer band produces rR enhancement patterns in the high frequency in-plane stretching region that directly probe the nature of this MLCT transition and provide insight into the effects of electron redistribution along the reaction coordinate between the transition state and the stable enzyme-product intermediate, including the role of the covalent Mo-O-C linkage in facilitating this process. The results clearly show that specific Mo-substrate orientations allow for enhanced electronic coupling and facilitate strong hydrogen bonding interactions with amino acid residues in the substrate binding pocket.

SUBMITTER: Yang J

PROVIDER: S-EPMC5634921 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Xanthine oxidase-product complexes probe the importance of substrate/product orientation along the reaction coordinate.

Yang Jing J Dong Chao C Kirk Martin L ML

Dalton transactions (Cambridge, England : 2003) 20171001 39

A combination of reaction coordinate computations, resonance Raman spectroscopy, spectroscopic computations, and hydrogen bonding investigations have been used to understand the importance of substrate orientation along the xanthine oxidase reaction coordinate. Specifically, 4-thiolumazine and 2,4-dithiolumazine have been used as reducing substrates for xanthine oxidase to form stable enzyme-product charge transfer complexes suitable for spectroscopic study. Laser excitation into the near-infrar ...[more]

PMID: 28696463

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Project description:The calculations of potential of mean force along complex chemical reactions or rare events pathways are of great interest because of their importance for many areas in chemistry, molecular biology, and material science. The major difficulty for free energy calculations comes from the great computational cost for adequate sampling of the system in high-energy regions, especially close to the reaction transition state. Here, we present a method, called FEG-RBD, in which the free energy gradients were obtained from rigid body dynamics simulations. Then the free energy gradients were integrated along a reference reaction pathway to calculate free energy profiles. In a given system, the reaction coordinates defining a subset of atoms (e.g., a solute, or the quantum mechanics (QM) region of a quantum mechanics/molecular mechanics simulation) are selected to form a rigid body during the simulation. The first-order derivatives (gradients) of the free energy with respect to the reaction coordinates are obtained through the integration of constraint forces within the rigid body. Each structure along the reference reaction path is separately subjected to such a rigid body simulation. The individual free energy gradients are integrated along the reference pathway to obtain the free energy profile. Test cases provided demonstrate both the strengths and weaknesses of the FEG-RBD method. The most significant benefit of this method comes from the fast convergence rate of the free energy gradient using rigid-body constraints instead of restraints. A correction to the free energy due to approximate relaxation of the rigid-body constraint is estimated and discussed. A comparison with umbrella sampling using a simple test case revealed the improved sampling efficiency of FEG-RBD by a factor of 4 on average. The enhanced efficiency makes this method effective for calculating the free energy of complex chemical reactions when the reaction coordinate can be unambiguously defined by a small subset of atoms within the system.

Dataset Information

Xanthine oxidase-product complexes probe the importance of substrate/product orientation along the reaction coordinate.

Publications

Xanthine oxidase-product complexes probe the importance of substrate/product orientation along the reaction coordinate.

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