https://www.frontiersin.org/articles/10.3389/fphar.2022.887991/full

ORIGINAL RESEARCH article

Front. Pharmacol., 25 May 2022 | https://doi.org/10.3389/fphar.2022.887991

Epigenetic Reader Bromodomain Containing Protein 2 Facilitates Pathological Cardiac Hypertrophy via Regulating the Expression of Citrate Cycle Genes

And

https://www.nature.com/articles/s42003-022-03416-7

Article

Open Access

Published: 19 May 2022

Differences in ligand-induced protein dynamics extracted from an unsupervised deep learning approach correlate with protein–ligand binding affinities

While our test cases were relatively rigid proteins that are widely used as benchmarks for free energy calculation, flexible proteins are interesting targets for further investigation. Dynamic properties may play a more important role in these systems. For a type of flexible protein, ligand-induced flexibility contributes to entropy gain in ligand binding, thus leading to higher affinity and longer residence of the ligands28. In fact, this was also seen in our cases in BRD4 with lig 4 (RVX-208) (Supplementary Fig. 10), where the binding is driven by entropy gain50. Furthermore, a similar approach could be used to study other protein–ligand binding events. For instance, it is interesting to evaluate the relationship between allosteric dynamics and ligand function, as has been done in a few previous studies22,39. Another potential application would be predicting the effects of protein mutations from the dynamics of the ligand. In this case, the relationship between the protein and ligand would be analyzed in a manner opposite to that employed in the present case, i.e., identical particles of the ligand would be used for LDE, while the protein molecules would vary slightly because of the mutation. We believe that the understanding of protein dynamics using ligand interactions will provide deeper insight into the function of ligands, and dynamics-based approaches would contribute to further developments in computational drug discovery.