Energetic Local Frustration Improves Protein-Ligand Docking Predictions

CLEMENTE CAMILA M; LEONETTI CESAR O; RAVETTI S; FERREIRO DIEGO U; PARRA R GONZALO; FREIBERGER MARÍA INÉS

Simposio; International Society for Computational Biology - LA SOIBIO BIONETMX 2020; 2020

Introduction While proteins fold, strong energetic conflicts are minimized as proteins adopt conformations more similar to their native states (minimum frustration principle). Local violations of this principle allow proteins to encode specific signals in their energy landscapes that are required to achieve their biological functions. Methods A non redundant data set of all monomeric enzymes with protein-ligand binding sites annotations were downloaded from the BioLiP database (n = 1007) in order to characterize protein-ligand interaction pockets. Protein structures were downloaded from the Protein Data Bank (PDB) and frustration patterns were calculated using the Frustratometer tool. We compared how well protein ligand interactions are predicted using both frustrapocket and fpocket. Results We predicted protein-ligand binding sites using fpocket and frustra-pocket in our dataset. We found that protein residues that directly interact with ligands are enriched in highly frustrated interactions.When taking frustration into account with our frustra pocket strategy, we improve the amount of predicted binding sites by 10%. Moreover, frustration permits to discriminate among multiple pocket predictions in a given protein and to give a per residue score for the constituting amino acids.