Insights into molecular interactions between CaM and its inhibitors from molecular dynamics simulations and experimental data

Abstract

In order to contribute to the structural basis for rational design of calmodulin (CaM) inhibitors, we analyzed the interaction of CaM with 14 classic antagonists and two compounds that do not affect CaM, using docking and molecular dynamics (MD) simulations, and the data were compared to available experimental data. The Ca²⁺-CaM-Ligands complexes were simulated 20 ns, with CaM starting in the “open” and “closed” conformations. The analysis of the MD simulations provided insight into the conformational changes undergone by CaM during its interaction with these ligands. These simulations were used to predict the binding free energies (ΔG) from contributions ΔH and ΔS, giving useful information about CaM ligand binding thermodynamics. The ΔG predicted for the CaM’s inhibitors correlated well with available experimental data as the r² obtained was 0.76 and 0.82 for the group of xanthones. Additionally, valuable information is presented here: I) CaM has two preferred ligand binding sites in the open conformation known as site 1 and 4, II) CaM can bind ligands of diverse structural nature, III) the flexibility of CaM is reduced by the union of its ligands, leading to a reduction in the Ca²⁺-CaM entropy, IV) enthalpy dominates the molecular recognition process in the system Ca²⁺-CaM-Ligand, and V) the ligands making more extensive contact with the protein have higher affinity for Ca²⁺-CaM. Despite their limitations, docking and MD simulations in combination with experimental data continue to be excellent tools for research in pharmacology, toward a rational design of new drugs.

Keywords:

• calmodulin
• protein-ligand interactions
• protein-peptide interactions
• MMPBSA
• molecular recognition
• docking
• molecular dynamics
• conformational flexibility

Acknowledgments

The authors are very grateful to Dr. A. Olson and his colleagues at the Scripps Research Institute for providing AutoDock. We are indebted to Dirección General de Cómputo y de Tecnologías de Información y Comunicación, UNAM, for providing the resources to carry out computational calculations through Nuevo Equipo de Supercomputo (NES) System and the project number SC14-1-I-36 Miztli supercomputer.

Disclosure statement

No potential conflict of interest was reported by the author.

Additional information

Funding

This work was supported by DGAPA-UNAM [grant number IN218110]; CONACyT [grant number 99395].