Unwinding the helical linker of calcium‐loaded calmodulin: A molecular dynamics study

Fiorin, Giacomo; Biekofsky, Rodolfo R.; Pastore, Annalisa; Carloni, Paolo

doi:10.1002/prot.20597

Cited by 31 publications

(57 citation statements)

References 78 publications

(170 reference statements)

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“…Misclassification, however, can also occur in these seemingly straightforward cases. For example, crystal packing may enforce certain disordered regions to become ordered [25], and disordered binding segments are often crystallized in complex with their partners and are classified ordered despite their lack of structure in isolation [26]. In addition, wobbly domains would appear disordered, despite their intrinsic structural order.…”

Section: Datasets For Order and Disordermentioning

confidence: 98%

Prediction of Protein Disorder at the Domain Level

Dosztányi¹,

Sándor²,

Tompa³

et al. 2007

CPPS

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Intrinsically disordered/unstructured proteins exist in a highly flexible conformational state largely devoid of secondary structural elements and tertiary contacts. Despite their lack of a well defined structure, these proteins often fulfill essential regulatory functions. The intrinsic lack of structure confers functional advantages on these proteins, allowing them to adopt multiple conformations and to bind to different binding partners. The structural flexibility of disordered regions hampers efforts solving structures at high resolution by X-ray crystallography and/or NMR. Removing such proteins/regions from high-throughput structural genomics pipelines would be of significant benefit in terms of cost and success rate. In this paper we outline the theoretical background of structural disorder, and review bioinformatic predictors that can be used to delineate regions most likely to be amenable for structure determination. The primary focus of our review is the interpretation of prediction results in a way that enables segmentation of proteins to separate ordered domains from disordered regions.

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Section: Datasets For Order and Disordermentioning

confidence: 98%

Prediction of Protein Disorder at the Domain Level

Dosztányi¹,

Sándor²,

Tompa³

et al. 2007

CPPS

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“…Several modeling studies and molecular dynamics (MD) simulations have been performed on CaM and they have been reviewed recently 3. In particular, MD simulations have been performed on the full‐length CaM (i) in the Ca 2+ ‐loaded form33–39; (ii) in the Ca 2+ ‐free form40; (iii) in the Ca 2+ ‐loaded form in complex with a target peptide 41. Also the central helix of CaM (fragment 65–92) has been analyzed using MD 35.…”

Section: Introductionmentioning

confidence: 99%

Conformational changes upon calcium binding and phosphorylation in a synthetic fragment of calmodulin

et al. 2006

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We have recently investigated by far-UV circular dichroism (CD) the effects of Ca(2+) binding and the phosphorylation of Ser 81 for the synthetic peptide CaM [54-106] encompassing the Ca(2+)-binding loops II and III and the central alpha helix of calmodulin (CaM) (Arrigoni et al., Biochemistry 2004, 43, 12788-12798). Using computational methods, we studied the changes in the secondary structure implied by these spectra with the aim to investigate the effect of Ca(2+) binding and the functional role of the phosphorylation of Ser 81 in the action of the full-length CaM. Ca(2+) binding induces the nucleation of helical structure by inducing side chain stacking of hydrophobic residues. We further investigated the effect of Ca(2+) binding by using near-UV CD spectroscopy. Molecular dynamics simulations of different fragments containing the central alpha-helix of CaM using various experimentally determined structures of CaM with bound Ca(2+) disclose the structural effects provided by the phosphorylation of Ser 81. This post-translational modification is predicted to alter the secondary structure in its surrounding and also to hinder the physiological bending of the central helix of CaM through an alteration of the hydrogen bond network established by the side chain of residue 81. Using quantum mechanical methods to predict the CD spectra for the frames obtained during the MD simulations, we are able to reproduce the relative experimental intensities in the far-UV CD spectra for our peptides. Similar conformational changes that take place in CaM [54-106] upon Ca(2+) binding and phosphorylation may occur in the full-length CaM.

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“…However in DCAM, the central linker of CaM2 unwinds and bends substantially in the Thr-79-Asp-80-Ser-81 region. This is consistent with the previous MD results of the Ca 2þ -loaded CaM monomer by Fiorin et al (2005). In accordance with what has been used in the literature (Vetter and Leclerc, 2003), the bending angle is defined as the angle between a pair of helical axes, in which the start and end points of the axes for our calculations are residues 65-79 for a helix and residues 81-89 for another helix in CaM2.…”

Section: Bending Of the Linker Region In Dcammentioning

confidence: 55%

“…X-ray crystallography or NMR) and by computer simulation, that the conformation of CaM changes considerably upon Ca 2þ binding to EF-hand motifs. The central a-helical linker increases in flexibility and unwinds (Fiorin et al, 2005). The relative position of a-helices in both calcium-binding domains is altered (Kunihiko et al, 2004).…”

Section: Introductionmentioning

confidence: 97%

Ligand‐induced dimer formation of calmodulin

Zhang

Tan

Jia

et al. 2008

J of Molecular Recognition

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Calmodulin (CaM) can bind to numerous proteins in several interaction modes. Recently a new mode of interaction was discovered, in which two CaM molecules form an X-shaped dimer and two binding sites to trap the CaM-binding domain (CBD) of calcineurin subunit A. However, the X-shaped CaM dimer alone without ligand has not been observed. We performed molecular dynamics (MD) simulations and used MM_PBSA approach to investigate the properties of this new binding mode using ligand-bound and -free dimer systems. MD trajectories show that two peptides of CBD play a critical role in stabilizing the X-shaped conformation of the CaM dimer which would otherwise be unstable, leading to dimer disassembly in the absence of the ligands. Furthermore, we have analyzed the interaction free energy of the complex by MM-PBSA method and provide further evidence to demonstrate that the CBD peptide ligands are responsible for the stabilization of the dimer. Comparing this new binding mode with the classical one represented by CaM in complex with smooth muscle myosin light chain kinase, we conclude that this new binding mode is induced by the CBD of calcineurin subunit A. Our results explain the fact that the X-shaped CaM dimer structure has never been observed in the absence of ligands.

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Unwinding the helical linker of calcium‐loaded calmodulin: A molecular dynamics study

Cited by 31 publications

References 78 publications

Prediction of Protein Disorder at the Domain Level

Prediction of Protein Disorder at the Domain Level

Conformational changes upon calcium binding and phosphorylation in a synthetic fragment of calmodulin

Ligand‐induced dimer formation of calmodulin

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