Ketosteroid isomerase (KSI) catalyzes steroid isomerization with extremely high efficiency and has become a paradigm of enzymatic proton transfer chemistry. In this work we show how the hydrogen bond network formed by KSI facilitates proton delocalization in the active site. By combining a series of recent advances we have performed ab initio path integral simulations of the KSI active site that incorporate the quantum nature of both the nuclei and electrons. This has allowed us to show that quantum delocalization of the protons in the hydrogen bond network greatly stabilizes the deprotonation of a key tyrosine residue in the active site and leads to a 10,000 fold increase in its acid dissociation constant. When a substrate analog is present, protons are delocalized along an extended hydrogen bond network which results in partial ionization of the substrate analog and various residues in the enzyme active site. This work indicates that KSI utilizes the quantum nature of the hydrogen bond network formed in its active site to stabilize the intermediate and achieve its remarkable catalytic power.

Quantum nature of the hydrogen bond network in the ketosteroid isomerase active site

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.