Revisiting allostery in CREB-binding protein (CBP) using residue-based interaction energy

Metin Yazar, Pemra Ozbek

J Comput Aided Mol Des (2020). https://doi.org/10.1007/s10822-020-00316-y

 

CREB-binding protein (CBP) is a multi-subunit scaffold protein complex in transcription regulation process, binding and interacting with ligands such as mixed-lineage leukemia (MLL) and c-Myb allosterically. Here in this study, we have revisited the concept of allostery in CBP via residue-based interaction energy calculation based on molecular dynamics (MD) simulations. To this end, we conducted MD simulations of KIX:MLL:c-Myb ternary complex, its binary components and kinase-inducible domain (KID) interacting domain (KIX) backbone. Interaction energy profiles and cross correlation analysis were performed and the results indicated that KIX:MLL and KIX:c-Myb:MLL complexes demonstrate significant similarities according to both analysis methods. Two regions in the KIX backbone were apparent from the interaction energy and cross correlation maps that hold a key to allostery phenomena observed in CBP. While one of these regions are related to the ligand binding residues, the other comprises of L12–G2 loop and α3 helix regions that have been found to have a significant role in allosteric signal propagation. All in all, residue-based interaction energy calculation method is demonstrated to be a valuable calculation technique for the detection of allosteric signal propagation and ligand interaction regions.