title: Molecular dynamics simulation of the calmodulin-trifluoperazine complex in aqueous solution.
abstract: Trifluoperazine (TFP) has been widely studied in relation to its mode of binding and its inactivation of calmodulin (CaM). Most studies in solution have indicated that CaM has two high-affinity binding sites for TFP. The crystal structure of the 1:4 CaM-TFP complex (CaM-4TFP) shows that three TFP molecules bind to the C-domain of CaM, and that one TFP molecule binds to the N-domain. In contrast, the crystal structure of the 1:1 CaM-TFP complex (CaM-1TFP) shows that one TFP molecule binds to the C-domain. It has been thought that the binding of one TFP molecule to the C-domain is followed by binding to the N-domain. The crystal structure of the 1:2 CaM-TFP complex (CaM-2TFP), moreover, has recently been determined, showing that two TFP molecules bind to the C-domain. In order to determine the structure of the CaM-TFP complex and to clarify the interaction between CaM and TFP in solution, we performed a molecular dynamics simulation of the CaM-TFP complex in aqueous solution starting from the CaM-4TFP crystal structure. The obtained solution structure is very similar to the CaM-2TFP crystal structure. The computer simulation showed that the binding ability of the secondary binding site of the C-domain is higher than that of the primary binding site of the N-domain.
authors.affiliation: Laboratory of Physical Chemistry for Drug Design, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641 Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yamaotsu
authors.forename: M
authors.initials: M
authors.lastname: Suga
authors.forename: S
authors.initials: S
authors.lastname: Hirono
mesh_terms: D001665:Binding Sites; D002147:Calmodulin / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D008958:Models, Molecular; D011487:Protein Conformation; D014268:Trifluoperazine / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D002147:Calmodulin; D014867:Water; D014268:Trifluoperazine