Department of

Computational Biological Chemistry

FWF P31024-N28: Effects of tautomerization on computed binding affinities

grant holderStefan Boresch
funding period04/2018 -


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