Exploring the Claisen Rearrangement and Aldol Reaction “on Water” and in Catalytic Antibodies using QM/MM Simulations and the Examination of Ligand Induced Conformational Changes in Alkanesulfonate Monooxygenase using Molecular Dynamics

Abstract

The “on water” environment, defined by the absence of water solubility of the reactants has been reported to provide increased rate accelerations, yields, and specificity for several types of organic reaction classes compared to organic solvents. The aromatic Claisen rearrangements of allyl p-R-phenyl ethers (R = CH3, Br, and OCH3) and allyl naphthyl ether, and another class of reaction, the aldol reaction have been investigated to determine their on water enhancements using QM/MM Monte Carlo calculations and free-energy perturbation theory. The aldol reaction was further studied in catalytic antibody 33F12 to determine the mechanistic properties and its comparison with the aldol reaction in condensed phase simulations. In another study, molecular dynamics calculations were performed on monooygenase systems to identify the protein fluctuations with various bound ligands (reduced flavin mononucleotide (FMNH2), a C4a-peroxyflavin intermediate, alkanesulfonate, FMNH2-alkanesulfonate, and C4a-peroxyflavin intemediate-alkanesulfonate) and an apo (free of ligand) structure. Salt bridge formations have been shown to participate in dynamic conformational changes for the ligand bound structures between Glu20-Arg297 and Asp111-Arg297. Also, Arg226 was confirmed to stabilize the peroxy group of the c4a-peroxyflavin ligand, and possibly help contributing to the sulfite release.