Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Biophys J
2006 May 01;909:3043-51. doi: 10.1529/biophysj.105.078071.
Show Gene links
Show Anatomy links
Protein grabs a ligand by extending anchor residues: molecular simulation for Ca2+ binding to calmodulin loop.
Kobayashi C
,
Takada S
.
???displayArticle.abstract???
The structural difference in proteins between unbound and bound forms directly suggests the importance of the conformational plasticity of proteins. However, pathways that connect two-end structures and how they are coupled to the binding reaction are not well understood at atomic resolution. Here, we analyzed the free-energy landscape, explicitly taking into account coupling between binding and conformational change by performing atomistic molecular dynamics simulations for Ca2+ binding to a calmodulin loop. Using the AMBER force field with explicit water solvent, we conducted umbrella sampling for the free-energy surface and steered molecular dynamics for the pathway search. We found that, at an early stage of binding, some key residue side chains extend their "arms" to catch Ca2+ and, after catching, they carry the Ca2+ to the center of the binding pocket. This grabbing motion resulted in smooth and stepwise exchange in coordination partners of Ca2+ from water oxygen to atoms in the calmodulin loop. The key residue that first caught the ion was one of the two acidic residues, which are highly conserved. In the pathway simulations, different pathways were observed between binding and dissociation reactions: The former was more diverse than the latter.
Allen,
Energetics of ion conduction through the gramicidin channel.
2004, Pubmed
Allen,
Energetics of ion conduction through the gramicidin channel.
2004,
Pubmed
Austin,
Dynamics of ligand binding to myoglobin.
1975,
Pubmed
Babu,
Determination of residue specificity in the EF-hand of troponin C for Ca2+ coordination, by genetic engineering.
1992,
Pubmed
Bracken,
Combining prediction, computation and experiment for the characterization of protein disorder.
2004,
Pubmed
Drake,
Molecular tuning of an EF-hand-like calcium binding loop. Contributions of the coordinating side chain at loop position 3.
1997,
Pubmed
Faga,
Basic interdomain boundary residues in calmodulin decrease calcium affinity of sites I and II by stabilizing helix-helix interactions.
2003,
Pubmed
Falke,
Molecular tuning of ion binding to calcium signaling proteins.
1994,
Pubmed
Frauenfelder,
The energy landscapes and motions of proteins.
1991,
Pubmed
Gerstein,
Exploring the range of protein flexibility, from a structural proteomics perspective.
2004,
Pubmed
Grubmüller,
Ligand binding: molecular mechanics calculation of the streptavidin-biotin rupture force.
1996,
Pubmed
Hobson,
Ligand-linked stability of mutants of the C-domain of calmodulin.
2005,
Pubmed
Izrailev,
Molecular dynamics study of unbinding of the avidin-biotin complex.
1997,
Pubmed
Jaren,
Paramecium calmodulin mutants defective in ion channel regulation can bind calcium and undergo calcium-induced conformational switching.
2000,
Pubmed
Komeiji,
Molecular dynamics simulations revealed Ca(2+)-dependent conformational change of Calmodulin.
2002,
Pubmed
Lopez,
The enthalpy of the alanine peptide helix measured by isothermal titration calorimetry using metal-binding to induce helix formation.
2002,
Pubmed
Marchand,
Molecular dynamics study of calbindin D9k in the apo and singly and doubly calcium-loaded states.
1998,
Pubmed
Matsuura,
Mutagenesis of the fourth calcium-binding domain of yeast calmodulin.
1993,
Pubmed
Maune,
Ca2+ binding and conformational change in two series of point mutations to the individual Ca(2+)-binding sites of calmodulin.
1992,
Pubmed
Merritt,
Raster3D: photorealistic molecular graphics.
1997,
Pubmed
Ouyang,
Metal ion binding to calmodulin: NMR and fluorescence studies.
1998,
Pubmed
Pedigo,
Quantitative endoproteinase GluC footprinting of cooperative Ca2+ binding to calmodulin: proteolytic susceptibility of E31 and E87 indicates interdomain interactions.
1995,
Pubmed
Pedigo,
Discontinuous equilibrium titrations of cooperative calcium binding to calmodulin monitored by 1-D 1H-nuclear magnetic resonance spectroscopy.
1995,
Pubmed
Rajamani,
Anchor residues in protein-protein interactions.
2004,
Pubmed
Schmidt,
Ligand migration pathway and protein dynamics in myoglobin: a time-resolved crystallographic study on L29W MbCO.
2005,
Pubmed
Shepherd,
A molecular dynamics study of Ca(2+)-calmodulin: evidence of interdomain coupling and structural collapse on the nanosecond timescale.
2004,
Pubmed
Shoemaker,
Speeding molecular recognition by using the folding funnel: the fly-casting mechanism.
2000,
Pubmed
Siedlecka,
Alpha-helix nucleation by a calcium-binding peptide loop.
1999,
Pubmed
Snyder,
Calcium(II) site specificity: effect of size and charge on metal ion binding to an EF-hand-like site.
1990,
Pubmed
Sorensen,
Interactions between domains of apo calmodulin alter calcium binding and stability.
1998,
Pubmed
Thorpe,
The coupling of structural fluctuations to hydride transfer in dihydrofolate reductase.
2004,
Pubmed
Vigil,
Functional dynamics of the hydrophobic cleft in the N-domain of calmodulin.
2001,
Pubmed
Wriggers,
Structure and dynamics of calmodulin in solution.
1998,
Pubmed
Wójcik,
Isolated calcium-binding loops of EF-hand proteins can dimerize to form a native-like structure.
1997,
Pubmed
Ye,
A grafting approach to obtain site-specific metal-binding properties of EF-hand proteins.
2003,
Pubmed
Ye,
Probing site-specific calmodulin calcium and lanthanide affinity by grafting.
2005,
Pubmed