Exploring chemical reaction mechanisms through harmonic Fourier beads path optimization

Abstract

Here, we apply the harmonic Fourier beads (HFB) path optimization method to study chemical reactions involving covalent bond breaking and forming on quantum mechanical (QM) and hybrid QM/molecular mechanical (QM/MM) potential energy surfaces. To improve efficiency of the path optimization on such computationally demanding potentials, we combined HFB with conjugate gradient (CG) optimization. The combined CG-HFB method was used to study two biologically relevant reactions, namely, L- to D-alanine amino acid inversion and alcohol acylation by amides. The optimized paths revealed several unexpected reaction steps in the gas phase. For example, on the B3LYP/6-31G(d,p) potential, we found that alanine inversion proceeded via previously unknown intermediates, 2-iminopropane-1,1-diol and 3-amino-3-methyloxiran-2-ol. The CG-HFB method accurately located transition states, aiding in the interpretation of complex reaction mechanisms. Thus, on the B3LYP/6-31G(d,p) potential, the gas phase activation barriers for the inversion and acylation reactions were 50.5 and 39.9 kcal/mol, respectively. These barriers determine the spontaneous loss of amino acid chirality and cleavage of peptide bonds in proteins. We conclude that the combined CG-HFB method further advances QM and QM/MM studies of reaction mechanisms.

Reliable and efficient reaction path and transition state finding for surface reactions with the growing string method

“…The algorithms designed to locate TSs and RPs are usually classified as single‐ended or double‐ended . Single‐ended methods start from a single initial state and refine it systematically to locate a TS.…”

β-Aminoalcohols as Potential Reactivators of Aged Sarin-/Soman-Inhibited Acetylcholinesterase

“…Recently, we reported the results of a mechanistic study of an unusual enzyme, CapD, from the superfamily of N‐terminal nucleophile (Ntn) hydrolases, which are functionally similar to AChE and serine proteases . These enzymes are also inhibited by phosphonylation .…”

“…To test whether the designed molecules could reactivate aged AChE, we used a multi‐tiered computational chemistry approach comprising 1 ) docking of a molecule into the active site of the aged AChE adduct, 2 ) molecular dynamic simulations of the complex in solution, and 3 ) hybrid quantum mechanical/molecular mechanical (QM/MM) reaction path calculations to assess the steps and energetics of aged AChE reactivation. Details of the approach are provided in the Supporting Information.…”

A Reaction Path Study of the Catalysis and Inhibition of theBacillus anthracisCapD γ-Glutamyl Transpeptidase

“…All required MM parameters were generated for the reactant states of both systems with the help of Antechamber from Amber Tools , and converted to the format required by Gaussian 09 (G09) software . We generated and optimized reaction paths using the Conjugate Gradient Harmonic Fourier Beads (CG-HFB) method . To generate smooth initial reaction paths, we performed a number of individual optimizations with progressive distance restraints to push the reactant states of both systems toward the tetrahedral intermediates and then toward the acylated enzymes.…”

“…In this paper, we studied the mechanism of CapD acylation by its native substrate pDGA and by the covalent inhibitor capsidin. Specifically, we applied docking and reaction path optimization on an ONIOM (our own N-layered integrated molecular orbital molecular mechanics) , hybrid quantum mechanical/molecular mechanical (QM/MM) potential energy surface . With the help of these computational tools, we identified the rate-limiting step in CapD acylation as the formation of the tetrahedral intermediate.…”