Fernandez Alberti, S. | Search bioRxiv

bioRxiv2023

Ghost interactions: revealing missing protein-ligand interactions using AlphaFold predictions

Protein-ligand interactions represent an essential step in understanding molecular recognition, an intense field of research for many scientific areas. Structural biology has played a central role in unveiling protein-ligand interactions, but current techniques are still not able to reliably describe the interactions of ligands with highly flexible regions. In this work we explored the capacity of AlphaFold2 (AF2) to estimate the presence of interactions between ligands and residues belonging to disordered regions, which we called "ghost interactions" as they are missing in the crystallographic derived structures. We found that AF2 models are good predictors of regions associated with order-disorder transitions. Additionally, we found that AF2 predicts residues making ghost interactions with ligands, which are mostly buried and show a differential evolutionary conservation. Our findings could fuel current areas of research that consider intrinsically disordered proteins as potentially valuable targets for drug development, given their biological relevance and associated diseases.

bioinformatics↗

bioRxiv2021

Impact of protein conformational diversity on AlphaFold predictions

After the outstanding breakthrough of AlphaFold in predicting protein 3D models, new questions appeared and remain unanswered. The ensemble nature of proteins, for example, challenges the structural prediction methods because the models should represent a set of conformers instead of single structures. The evolutionary and structural features captured by effective deep learning techniques may unveil the information to generate several diverse conformations from a single sequence. Here we address the performance of AlphaFold2 predictions under this ensemble paradigm. Using a curated collection of apo-holo conformations, we found that AlphaFold2 predicts the holo form of a protein in 70% of the cases, being unable to reproduce the observed conformational diversity with an equivalent error than in the estimation of a single conformation. More importantly, we found that AlphaFold2s performance worsens with the increasing conformational diversity of the studied protein. This impairment is related to the heterogeneity in the degree of conformational diversity found between different members of the homologous family of the protein under study. Finally, we found that main-chain flexibility associated with apo-holo pairs of conformers negatively correlates with the predicted local model quality score plDDT, indicating that plDDT values in a single 3D model could be used to infer local conformational changes linked to ligand binding transitions.

bioinformatics↗