Tryptophan Stabilization of a Biochemical Carbocation Evaluated by Analysis of π Complexes of 3-Ethylindole with the t-Butyl Cation.

Abstract

Understanding how the highly unstable carbocation intermediates in terpenoid biosynthesis are stabilized and protected during their transient existence in enzyme active sites is an intriguing challenge which has to be addressed computationally. Our efforts have focused on evaluating the stabilization afforded via carbocation-π complexation between a biochemical carbocation and an aromatic amino acid residue. This has involved making measurements on an X-ray structure of an enzyme active site that shows a π donor proximate to a putative carbocation site and using these to build models which are analyzed computationally to provide an estimated stabilization energy (SE). Previously, we reported estimated SEs for several such carbocation-π complexes involving phenylalanine. Herein, we report the first such estimate involving tryptophan as the π donor. Because there was almost no published information about indole as a π-complexation donor, we first located computationally equilibrium π and σ complexes of 3-ethylindole with the t-butyl cation as relevant background information. Then, measurements on the X-ray structure of the enzyme CotB2 complexed with geranylgeranyl thiodiphosphate (GGSPP), specifically on the geometric relationship of the putative carbocation at C15 of GGSPP to W186, were used to build a model that afforded a computed SE of -15.3 kcal/mol.