FWF P31024-N28: Effects of tautomerization on computed binding affinities
grant holder
Stefan Boresch
funding period
04/2018 -
Abstract
One central task of computer aided molecular design is to identify potentially active compounds against specific molecular targets,
which have been identified as relevant for the pathobiology of an illness. Only those compounds predicted to have sufficient activity
then need to be synthesized and tested experimentally, thus saving time and cost. For a few years now, so-called “free energy
simulations” have been in widespread use, and, in principle, provide an accurate method to predict the binding free energy of
ligands/inhibitors to a target molecule, typically a protein. Knowing relevant free energy differences is important as
they are the fundamental criterion whether a reaction, such as binding of a ligand to a target molecule, takes place voluntarily or not.
Free energy simulations are the most costly computational methods among the tools available for screening large numbers of compounds
and are used as the last step before experimental tests are carried out. Therefore, it is quite important that results obtained in such
calculations are accurate. The predictive value (i.e., accuracy of results) of such calculations depends on a number of factors. One
possible source of error is the presence of what chemists denote as multiple tautomeric forms of a molecule. Two tautomeric forms of a
molecule contain identical types and numbers of atoms; however, their molecular structure typically differs by the location of a
hydrogen atom. In parallel, the position of a double bond changes as well. Tautomeric states of a molecule may have different
physico-chemical properties, which may also affect their binding affinities. Thus, if the presence of an alternative tautomeric form
is overlooked when carrying out a free energy simulation, a systematic error may occur, and available evidence suggests that
said error may be considerable.
Interestingly, this potential source of error in free energy simulations has to date not been investigated in much detail. This
project aims to address the influence of tautomeric forms on binding affinities computed by free energy simulations in three
steps. First, we want to compute free energy differences of binding for different tautomeric states to a number of systems, which will
allow us to understand the size of this potential error more systematically. Second, at the methodological level, there are
different approaches that can be used to account for the presence of tautomeric states in free energy simulations, and we want to explore
which is the most efficient one. Finally, it is not clear that the classical mechanical force fields used to describe interactions
between atoms and molecules in free energy simulations are sufficient to account for the influence of tautomeric states. Therefore,
we will also use hybrid methods in which a small region of particular interest is studied by quantum chemical methods
(specifically the compound existing in two or more tautomeric forms), whereas the rest of the systems would be described by the
usual force fields.
Imprint:
(as stipulated by Austrian law, MedienG 2005):
S. Boresch / C. Schröder,
Institut für Computergestützte Biologische Chemie,
Währinger Strasse 17, 1090 Wien, Austria