Three-dimensional structures of protein-ligand complexes are an essential and commonly used basis in drug discovery. Unfortunately, the most frequently applied experimental technique for the resolution of macromolecular structures, X-ray crystallography, comes along with some uncertainties in the evaluation of hydrogen positions and discrimination of similar chemical elements. Existing software tools cover the unresolved structural properties of proteins quite well, various relevant degrees of freedom remain unconsidered for ligand molecules. Especially neglecting tautomers and protonation states of ligands may result in suboptimal hydrogen-bond networks at the protein-ligand interface. Based on our hydrogen placement algorithm Protoss, we developed a novel approach incorporating alternative tautomers and protonation states for ligand molecules. With this, Protoss is to our knowledge the first method covering the whole spectrum of hydrogen variability in protein-ligand complexes automatically.

Prediction of tautomers and protonation states in protein-ligand binding sites

247th National Meeting (2014)

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