Quantum mechanics and molecular mechanics study of the reaction mechanism of quorum quenching enzyme: N-acyl homoserine lactonase with C6-HSL

Abstract

N-Acyl-homoserine lactonase from Ochrobactrum sp. strain (AidH) is a novel AHL (N-acyl-homoserine lactone)-lactonase that hydrolyzes the ester bond of the homoserine lactone ring of AHLs. In this article, on the basis of the high-resolution crystal structure of the mutated AidH in complex with substrate, a combined quantum mechanics/molecular mechanics (QM/MM) approach has been employed to study the detailed catalytic mechanism of AidH using C6-HSL (N-hexanoyl homoserine lactone) as the substrate. The calculation results reveal that the catalytic reaction starts from the abstraction of the hydroxyl hydrogen of Ser102 by His248. Both the formation and cleavage of the covalent bond between Ser102 and the substrate are possible rate-limiting steps, corresponding to energy barriers of 19.2 and 21.7 kcal mol⁻¹, respectively. The ring-opening of the covalent intermediate is calculated to be quite easy. During the catalysis, His248 acts as a dual Lewis acid/base, whereas Glu219 is not directly involved in the chemical process and Tyr160 only plays a role in stabilizing the transition state and orienting the position of the hydrolytic water molecule. In addition, the distant surrounding residues were found to have different influences on the reaction by their electrostatic interaction with the substrate. These results may provide useful information for the novel treatment of plant and animal infections that rely on AHL signaling.