Nov 13
2019

Hydrogens Matter - A look at modern pKa and tautomer prediction

Dr. Stephan Ehrlich

Senior Scientist, Applications Science
Summary

Tautomers and protomers are omnipresent in biological systems. Protein side chains, natural substrates, or designed drugs all have in common that their tautomeric and protonation state drive key interactions via hydrogen bonds and salt bridges.

In drug design, understanding of these different states of a molecule is key, since they will drive properties like solubility, membrane permeability, and of course activity.

When applying atomistic modeling, modelers commonly have to decide on a specific state, which in turn has a direct impact on the accuracy of the model and the insights that can be derived from it. While many good empirical models exist to predict the correct tautomeric and protonation state of drug-like molecules, they often fail when stereochemistry is important or when exploring new chemical space.

The presentation will highlight quantum mechanics based tools and workflows within Schrödinger software to alleviate that problem. It will also showcase where traditional methods fail, and give guidelines on when to switch to more accurate methods. Finally, we will circle back to molecular mechanics, and show how these calculations can enhance our accurate free energy perturbation methods (FEP+) to correctly describe systems with multiple relevant protonation and tautomer states.

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