A comprehensive understanding of
structure–reactivity relationships
is critical to the design and optimization of cysteine-targeted covalent
inhibitors. Herein, we report glutathione (GSH) reaction rates for N-phenyl acrylamides with varied substitutions at the α-
and β-positions of the acrylamide moiety. We find that the GSH
reaction rates can generally be understood in terms of the electron
donating or withdrawing ability of the substituent. When installed
at the β-position, aminomethyl substituents with amine pK
a’s > 7 accelerate, while those with
pK
a’s < 7 slow the rate of GSH
addition at pH 7.4, relative to a hydrogen substituent. Although a
computational model was able to only approximately capture experimental
reactivity trends, our calculations do not support a frequently invoked
mechanism of concerted amine/thiol proton transfer and C–S
bond formation and instead suggest that protonated aminomethyl functions
as an electron-withdrawing group to reduce the barrier for thiolate
addition to the acrylamide.
In this paper we present embedded-cluster calculations on
singly charged and neutral oxygen vacancies (or F centres) in the
oxide perovskite BaTiO3. The simulations include Hartree-Fock
theory with MP2 corrections and density-functional-theory
calculations for a central quantum defect cluster and a
pair-potential description of the embedding lattice. All important
defect-induced lattice distortions are taken into account in this
way. We discuss the possible electronic states of charged F centres
and the effects of nearby acceptor-type defects. It is shown that
isolated oxygen vacancies induce electronic deep-gap levels.
Scenarios are discussed to account for shallow-gap levels observed
experimentally.
Optimization of a transition state typically requires both a good initial guess of the molecular structure and one or more computationally demanding Hessian calculations to converge reliably. Often, the transition state being optimized corresponds to the barrier in a chemical reaction where bonds are being broken and formed. Utilizing the geometries and bonding information for reactants and products, an algorithm is outlined to reliably interpolate an initial guess for the transition state geometry. Additionally, the change in bonding is also used to increase the reliability of transition state optimizations that utilize approximate and updated Hessian information. These methods are described and compared against standard transition state optimization methods.
The development of algorithms to optimize reaction pathways between reactants and products is an active area of study. Existing algorithms typically describe the path as a discrete series of images (chain of states) which are moved downhill toward the path, using various reparameterization schemes, constraints, or fictitious forces to maintain a uniform description of the reaction path. The Variational Reaction Coordinate (VRC) method is a novel approach that finds the reaction path by minimizing the variational reaction energy (VRE) of Quapp and Bofill. The VRE is the line integral of the gradient norm along a path between reactants and products and minimization of VRE has been shown to yield the steepest descent reaction path. In the VRC method, we represent the reaction path by a linear expansion in a set of continuous basis functions and find the optimized path by minimizing the VRE with respect to the linear expansion coefficients. Improved convergence is obtained by applying constraints to the spacing of the basis functions and coupling the minimization of the VRE to the minimization of one or more points along the path that correspond to intermediates and transition states. The VRC method is demonstrated by optimizing the reaction path for the Müller-Brown surface and by finding a reaction path passing through 5 transition states and 4 intermediates for a 10 atom Lennard-Jones cluster.
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