Comparing atom-based with residue-based descriptors in predicting binding site similarity: do backbone atoms matter?

Abstract

We question the level of detail required in protein 3D-representation to detect site similarity which is relevant for polypharmacology prediction. We modified the in-house program SiteAlign to replace generic pharmacophoric descriptors of cavity-lining amino acids by descriptors accounting for solvent exposure. Benchmarking the novel, atom-based, method (SiteAlign2) revealed no global improvement of performance. However, in the rare cases of no sequence or global structure similarities between the compared proteins, SiteAlign2 was more successful if backbone atoms are key determinants of ligand binding. SiteAlign suits the comparison of binding sites for close or distant homologs. SiteAlign2 provides a better insight into the physical model of site similarity between nonhomologs, but at the expense of an increased sensitivity to atomic coordinates.