Composition of Overlapping Protein-Protein and Protein-Ligand Interfaces

Abstract

Protein-protein interactions (PPIs) play a major role in many biological processes and they represent an important class of targets for therapeutic intervention. However, targeting PPIs is challenging because often no convenient natural substrates are available as starting point for small-molecule design. Here, we explored the characteristics of protein interfaces in five non-redundant datasets of 174 protein-protein (PP) complexes, and 161 protein-ligand (PL) complexes from the ABC database, 436 PP complexes, and 196 PL complexes from the PIBASE database and a dataset of 89 PL complexes from the Timbal database. In all cases, the small molecule ligands must bind at the respective PP interface. We observed similar amino acid frequencies in all three datasets. Remarkably, also the characteristics of PP contacts and overlapping PL contacts are highly similar.

A systematic analysis of atomic protein–ligand interactions in the PDB

“…Among the most frequently observed are interactions that are well known and widely used in ligand design such as hydrophobic contacts, hydrogen bonds and π-stacking. 18 , 19 These are followed by weak hydrogen bonds, salt bridges, amide stacking, and cation–π interactions.…”

Computational Assessment of Bacterial Protein Structures Indicates a Selection Against Aggregation

“…The aromatic residues (phenylalanine, tyrosine and tryptophan) were enriched in aggregation-prone structures (Figure 10). This can be related to the fact that exposed aromatic residues facilitate protein–protein interactions and indeed these three residues are more frequent at protein interfaces than at their surfaces [59]. This property can be partially explained by their ability to establish both π–π or π–cation interactions, their flat surfaces and the entropic benefit of hiding them from water inside interfaces.…”

CATH functional families predict functional sites in proteins

“…The three predictors were run separately, instead of combining them into a single model, because the functional plasticity of residues (Dessailly et al, 2013) means that, depending on its context, a residue can perform multiple functions. For example, some proteins often use the same or overlapping set of surface residues to bind small molecules and other proteins (Davis & Sali, 2010;Mohamed, Degac, & Helms, 2015). Moreover, an increasing number of proteins have been found to perform multiple molecular functions using different, overlapping or sometimes the same set of residues (Das, Khan, Kihara, & Orengo, 2017).…”