Application of QM/MM and QM methods to investigate histone deacetylase 8

Abstract

Computational chemistry plays an important supporting role in the early stages of drug discovery research. Such methods are not without flaws, however they can be very useful in the development and testing of hypothesises as well as prioritizing aspects of the exploration process. In this paper we discuss some common issues with employing hybrid quantum mechanical/molecular mechanical (QM/MM) methods in certain drug discovery applications. The QM/MM method provides a means to simulate large biological systems for moderate computational cost. We use the method to assess the metalloproteins, human deacetylases (HDACs), which are targets for a variety of medical conditions including neurodegenerative diseases and HIV infection. Metalloproteins in particular are a challenge to simulate using the rapid empirical methods preferred in the pharmaceutical industry. We report the use of a QM/MM scheme of only moderate computational cost to explore the active site as well as its catalytic reaction. We also demonstrate the value of the method over smaller QM clusters and show that the method is capable of describing the kinetic differences associated with replacing Zn²⁺ with other metal co-factors.