Computational Simulations of DNA Transaction Enzymes: Application and Development
Project Summary
Computational simulations based on classical molecular dynamics (MD) and hybrid quantum mechanical
(QM)/molecular mechanical (MM) methods have been shown to provide a very important tool to investigate the
reaction mechanism of enzymes with atomic level detail. Our long-term goal is to develop accurate QM/MM
methods to understand the mechanism, structure and function of enzymes involved in DNA transactions by
computational simulations. Both of these approaches have been pivotal to achieve detailed understanding of
certain aspects of DNA transaction enzymes. The accurate synthesis, maintenance, repair, and modification of
DNA is crucial for organismal survival since errors in DNA can lead to the onset of different diseases.
Therefore, enzymes related to DNA transactions need to perform their activities accurately and efficiently.
Mutations arising from exogenous or endogenous factors can result in changes that affect the structure and/or
function of these enzymes. There are a large number of enzyme families involved in the synthesis, repair and
modification of DNA. To this end, the goals of the present proposal are: 1) To improve the accuracy of
computational simulations by continuing the development of LICHEM, our QM/MM software, which interfaces
QM programs with advanced anisotropic/polarizable force fields (GEM and AMOEBA) to accurately describe
the MM environment; and to improve the sampling of QM/MM simulations using machine learning approaches
for applications with polarizable force fields. 2) To apply these techniques to understand evolutionary
convergence of function on DNA synthesis proteins; how distal mutations affect these functions and other
functions on DNA synthesis and other DNA transaction enzymes; and exploit this knowledge to develop
inhibitors that can be used as therapeutics for specific DNA polymerases and iron/2-oxoglutarate enzymes
related to DNA transactions.