title: Interaction of antagonists with calmodulin: insights from molecular dynamics simulations.
abstract: We report results of 12 ns, all-atom molecular dynamics simulation (MDS) and Poisson-Boltzmann free energy calculations (PBFE) on calmodulin (CaM) bound to two molecules of trifluoperazine (TFP) and of N-(3,3, diphenylpropyl)- N'-[1- R-(3,4-bis-butoxyphenyl)-ethyl]-propylenediamine (DPD). X-ray data show very similar structures for the two complexes, yet the antagonists significantly differ with respect to their CaM binding affinities, the neutral DPD is much more potent. The goal of the study was to unravel the reason why TFP is less potent although its positive charge should facilitate binding. The electrostatic energy terms in CHARMM and binding free energy terms of the PBFE approach showed TFP a better antagonist, while inspection of hydrophobic contacts supports DPD binding. Detailed inspection of the amino acid contributions of PBFE calculations unravel that steric reasons oppose the favorable binding of TFP. Structural conditions are given for a successful drug design strategy, which may benefit also from charge-charge interactions.
authors.affiliation: Department of Biophysics and Radiation Biology and Research Group for Membrane Biology, Hungarian Academy of Sciences, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Kövesi
authors.forename: Dóra K
authors.initials: DK
authors.lastname: Menyhárd
authors.forename: Monique
authors.initials: M
authors.lastname: Laberge
authors.forename: Judit
authors.initials: J
authors.lastname: Fidy
mesh_terms: D001665:Binding Sites; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D003198:Computer Simulation; D005275:Fendiline / Q000031:analogs & derivatives* / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D055672:Static Electricity; D013816:Thermodynamics; D014268:Trifluoperazine / Q000737:chemistry*
chemical_list: D002147:Calmodulin; C407023:N-(3,3-diphenylpropyl)-N'-(1-(3,4-bis(butoxyphenyl))ethyl)propylenediamine; D014268:Trifluoperazine; D005275:Fendiline