title: Unwinding the helical linker of calcium-loaded calmodulin: a molecular dynamics study.
abstract: The fold of calmodulin (CaM) consists of two globular domains connected by a helical segment (the linker), whose conformational properties play a crucial role for the protein's molecular recognition processes. Here we investigate the structural properties of the linker by performing a 11.5 ns molecular dynamics (MD) simulation of calcium-loaded human CaM in aqueous solution. The calculations are based on the AMBER force field. The calculated S2 order parameters are in good accord with NMR data: The structure of the linker in our simulations is much more flexible than that emerging from the Homo sapiens X-ray structure, consistently with the helix unwinding observed experimentally in solution. This process occurs spontaneously in a nanosecond timescale, as observed also in a very recent simulation based on the GROMOS force field. A detailed description of the mechanism that determines the linker unwinding is provided, in which electrostatic contacts between the two globular domains play a critical role. The orientation of the domains emerging from our MD calculations is consistent both with former X-ray scattering data and a recent NMR work. Based on our findings, a rationale for the experimentally measured entropy cost associated to binding to the protein's cellular partners is also given.
authors.affiliation: SISSA-International School for Advanced Studies, INFM-Democritos Modeling Center for Research in Atomistic Simulation, Trieste, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Fiorin
authors.forename: R R
authors.initials: RR
authors.lastname: Biekofsky
authors.forename: A
authors.initials: A
authors.lastname: Pastore
authors.forename: P
authors.initials: P
authors.lastname: Carloni
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011485:Protein Binding; D011489:Protein Denaturation; D017433:Protein Structure, Secondary
chemical_list: D002147:Calmodulin; D002118:Calcium