title: 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 Ca(2+)-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 r(2) 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 Ca(2+)-CaM entropy, IV) enthalpy dominates the molecular recognition process in the system Ca(2+)-CaM-Ligand, and V) the ligands making more extensive contact with the protein have higher affinity for Ca(2+)-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.
authors.affiliation: a Facultad de Medicina , Universidad Nacional Autónoma de México (UNAM) , México Distrito Federal , CP 04510 , México.|c Unidad de Vinculación de la Facultad de Medicina , UNAM en el INMEGEN , Secretaría de Salud, México Distrito Federal , CP 14610 , México.
authors.forename: Martin
authors.initials: M
authors.lastname: González-Andrade
authors.affiliation: b Facultad de Química , Universidad Nacional Autónoma de México (UNAM) , México Distrito Federal , CP 04510 , México.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Rodríguez-Sotres
authors.affiliation: b Facultad de Química , Universidad Nacional Autónoma de México (UNAM) , México Distrito Federal , CP 04510 , México.
authors.forename: Abraham
authors.initials: A
authors.lastname: Madariaga-Mazón
authors.affiliation: b Facultad de Química , Universidad Nacional Autónoma de México (UNAM) , México Distrito Federal , CP 04510 , México.
authors.forename: José
authors.initials: J
authors.lastname: Rivera-Chávez
authors.affiliation: b Facultad de Química , Universidad Nacional Autónoma de México (UNAM) , México Distrito Federal , CP 04510 , México.
authors.forename: Rachel
authors.initials: R
authors.lastname: Mata
authors.affiliation: a Facultad de Medicina , Universidad Nacional Autónoma de México (UNAM) , México Distrito Federal , CP 04510 , México.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sosa-Peinado
authors.affiliation: c Unidad de Vinculación de la Facultad de Medicina , UNAM en el INMEGEN , Secretaría de Salud, México Distrito Federal , CP 14610 , México.
authors.forename: Luis
authors.initials: L
authors.lastname: Del Pozo-Yauner
authors.affiliation: d Unidad de Biología Molecular y Medicina Genómica del Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México (UNAM) , México Distrito Federal , CP 04510 , México.|e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , México Distrito Federal , CP 14000 , México.
authors.forename: Imilla I
authors.initials: II
authors.lastname: Arias-Olguín
mesh_terms: D001583:Benzoxazoles; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008301:Maleimides; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects*; D013816:Thermodynamics
chemical_list: C474746:5-maleimidyl-2-(m-methylphenyl)benzoxazol; D001583:Benzoxazoles; D002147:Calmodulin; D008024:Ligands; D008301:Maleimides; D002118:Calcium
keywords: MMPBSA; calmodulin; conformational flexibility; docking; molecular dynamics; molecular recognition; protein-ligand interactions; protein-peptide interactions