Using ab initio molecular dynamics (AIMD) simulations that treat rare events, we probe the active site participation in the rate-determining H-transfer step in the oxidation of linoleic acid by soybean lipoxygenase-1 (SLO-1). (a) On the H-transfer acceptor side, the H-bonding propensity between the acceptor-OH, bound to the Fe-cofactor, and the backbone CO of isoleucine (I839) positively influences the H-transfer event. With increasing average nuclear kinetic energy, the transfer probability is enhanced due to presence of the H-bond between the backbone-carbonyl of I839 and acceptor-OH. Further increase in average nuclear kinetic energy reduces the H-bond strength and deteriorates the H-transfer rate. (b) On the donor side, the coupling between vibrational modes predominantly localized on the donor-side linoleic acid group and the reactive mode is probed. There is a qualitative difference in the coupling between modes that belong to linoleic acid and H-transfer modes, for H- and D-transfer. Donor side secondary H-atom is much more labile during D-transfer compared to H-transfer. This greater coupling between the modes belonging to the linoleic acid and the D-transfer mode provides a new rationalization for the abnormal (nonclassical) secondary isotope effect results obtained by Klinman.

Active site dynamical effects in the hydrogen transfer rate-limiting step in the catalysis of linoleic acid by soybean lipoxygenase-1 (SLO-1): Primary and secondary isotope contributions

256th National Meeting (2018)

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