Quantum Delocalization of Protons in the Ketosteroid Isomerase Active Site

Abstract

Ketosteroid isomerase (KSI) catalyzes steroid isomerization with extremely high efficiency and has become a paradigm of enzymatic proton transfer chemistry. In this poster I will show our recent research which has identified how the hydrogen bond network formed by this enzyme facilitate proton delocalization and sharing in the active site. This quantum delocalization greatly stabilizes a deprotonated tyrosine residue in the active site and leads to a 10,000 fold increase in its acid dissociation constant. This study is made possible by a series of technical breakthroughs developed in our group that greatly enhance the efficiency of including quantum mechanical fluctuations in simulating condensed phase systems and extracting isotope effects. These advances allow us to investigate the quantum delocalization of protons in the active site of KSI, which might shed light on the origin of the enzyme's remarkable catalytic efficiency and guide the development of synthetic catalysts.