title: Conformational frustration in calmodulin-target recognition.
abstract: Calmodulin (CaM) is a primary calcium (Ca(2+) )-signaling protein that specifically recognizes and activates highly diverse target proteins. We explored the molecular basis of target recognition of CaM with peptides representing the CaM-binding domains from two Ca(2+) -CaM-dependent kinases, CaMKI and CaMKII, by employing experimentally constrained molecular simulations. Detailed binding route analysis revealed that the two CaM target peptides, although similar in length and net charge, follow distinct routes that lead to a higher binding frustration in the CaM-CaMKII complex than in the CaM-CaMKI complex. We discovered that the molecular origin of the binding frustration is caused by intermolecular contacts formed with the C-domain of CaM that need to be broken before the formation of intermolecular contacts with the N-domain of CaM. We argue that the binding frustration is important for determining the kinetics of the recognition process of proteins involving large structural fluctuations.
authors.affiliation: Department of Physics, University of Houston, Houston, TX, 77204, USA; Center for Theoretical Biological Physics, Rice University, Houston, TX, 77005, USA.
authors.forename: Swarnendu
authors.initials: S
authors.lastname: Tripathi
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Pengzhi
authors.initials: P
authors.lastname: Zhang
authors.forename: Laurel
authors.initials: L
authors.lastname: Hoffman
authors.forename: M Neal
authors.initials: MN
authors.lastname: Waxham
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Cheung
mesh_terms: D000818:Animals; D001665:Binding Sites; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D002147:Calmodulin; D010455:Peptides; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: binding frustration; binding route analysis; calmodulin; calmodulin-binding targets; coarse-grained molecular simulations; protein-protein association; target recognition