M. Ikura and J. B. Ames, Genetic polymorphism and protein conformational plasticity in the calmodulin superfamily: two ways to promote multifunctionality, Proc. Natl. Acad. Sci. U.S.A, vol.103, pp.1159-1164, 2006.

D. Chin and A. R. Means, Calmodulin: a prototypical calcium sensor, Trends Cell Biol, vol.10, pp.322-328, 2000.

L. Van-eldik and D. Watterson, Calmodulin and Signal Transduction, 1998.

H. J. Vogel, Calmodulin: a versatile calcium mediator protein, Biochem. Cell. Biol, vol.72, pp.357-376, 1994.

N. V. Valeyev, D. G. Bates, P. Heslop-harrison, I. Postlethwaite, and N. V. Kotov, Elucidating the mechanisms of cooperative calcium-calmodulin interactions: a structural systems biology approach, BMC Syst. Biol, vol.2, p.48, 2008.

A. Crivici and M. Ikura, Molecular and structural basis of target recognition by calmodulin, Annu. Rev. Biophys. Biomol. Struct, vol.24, pp.85-116, 1995.

H. Weinstein and E. L. Mehler, Ca 2+ -binding structural dynamics in functions of calmodulin, Annu. Rev. Physiol, vol.56, pp.213-236, 1994.

Y. S. Babu, J. S. Sack, T. J. Greenhough, C. E. Bugg, A. R. Means et al., 3-dimentional structure of calmodulin, Nature, vol.315, p.37, 1985.

B. E. Finn, J. Evenas, T. Drakenberg, J. P. Waltho, E. Thulin et al., Calcium-induced structural changes and domain autonomy in calmodulin, Interplay between EF-CaM and Ca 2+ -CaM, vol.2, p.20, 1995.

H. Kuboniwa, N. Tjandra, S. Grzesiek, H. Ren, C. B. Klee et al., Solution structure of calcium-free calmodulin, Nat. Struct. Biol, vol.2, pp.768-776, 1995.

M. Zhang, T. Tanaka, and M. Ikura, Calcium-induced conformational transition revealed by the solution structure of apo calmodulin, Nat. Struct. Biol, vol.2, pp.758-767, 1995.

H. Ishida, K. Takahashi, K. Nakashima, Y. Kumaki, M. Nakata et al., Solution structures of the N-terminal domain of yeast calmodulin: Ca 2+ -dependent conformational change and its functional implication, Biochemistry, vol.39, pp.13660-13668, 2000.

R. C. Liddington, Anthrax: a molecular full nelson, Nature, vol.415, pp.373-374, 2002.

C. L. Drum, S. Z. Yan, J. Bard, Y. Q. Shen, D. Lu et al., Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin, Nature, vol.415, pp.396-402, 2002.

T. S. Ulmer, S. Soelaiman, S. Li, C. B. Klee, W. J. Tang et al., Calcium dependence of the interaction between calmodulin and anthrax edema factor, J. Biol. Chem, vol.278, pp.29261-29266, 2003.

E. Laine, J. D. Yoneda, A. Blondel, and T. E. Malliavin, The conformational plasticity of calmodulin upon calcium complexation gives a model of its interaction with the oedema factor of Bacillus anthracis, Proteins, vol.71, pp.1813-1829, 2008.

H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat et al., The Protein Data Bank, Nucleic Acids Res, vol.28, pp.235-242, 2000.

Y. Shen, N. L. Zhukovskaya, Q. Guo, J. Florián, and W. J. Tang, Calciumindependent calmodulin binding and two-metal-ion catalytic mechanism of anthrax edema factor, EMBO J, vol.24, pp.929-941, 2005.

D. A. Case, T. A. Darden, T. E. Cheatham, C. L. Simmerling, J. Wang et al., , 2004.

J. Aqvist, Ion-water interaction potentials derived from free energy perturbation simulations, J. Phys. Chem, vol.94, pp.8021-8024, 1990.

G. Fiorin, R. R. Biekofsky, A. Pastore, and P. Carloni, Unwinding the helical linker of calcium-loaded calmodulin: a molecular dynamics study, Proteins, vol.61, pp.829-839, 2005.

D. A. Case, T. A. Darden, T. E. Cheatham, C. L. Simmerling, J. Wang et al., , 2006.

A. Lewit-bentley and S. Rety, EF-hand calcium-binding proteins, Curr Opin Struct Biol, vol.10, pp.637-643, 2000.

M. F. Sanner, A. J. Olson, and J. C. Spehner, Fast and robust computation of molecular surfaces, Proc. 11th ACM Symp. Comp. Geom, pp.6-7, 1995.

I. K. Mcdonald and J. M. Thornton, Satisfying hydrogen bonding potential in proteins, J. Mol. Biol, vol.238, pp.777-793, 1994.

A. C. Wallace, R. A. Laskowski, and J. M. Thornton, LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions, Prot. Eng, vol.8, pp.127-134, 1995.

, R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, 2006.

W. Humphrey, A. Dalke, and K. Schulten, VMD: visual molecular dynamics, J. Mol. Graph, vol.14, pp.27-28, 1996.

W. L. Delano, The pymol molecular graphics system, 2002.

P. Emsley and K. Cowtan, Coot: model-building tools for molecular graphics, Acta Crystallographica Section D-Biological Crystallography, vol.60, pp.2126-2132, 2004.

A. A. Vagin, R. A. Steiner, A. A. Lebedev, L. Potterton, S. Mcnicholas et al., REFMAC5 dictionary: organization of prior chemical knowledge and guidelines for its use, Acta Crystallogr. D Biol. Crystallogr, vol.60, pp.2184-2195, 2004.

B. R. Brooks, R. E. Bruccoleri, B. D. Olafson, D. J. States, S. Swaminathan et al., CHARMM -A program for macromolecular energy, minimization, and dynamics calculations, J. Comp. Chem, vol.4, pp.187-217, 1983.

R. Lavery, H. Sklenar, K. Zakrzewska, and B. Pullman, The flexibility of the nucleic acids: (II). The calculation of internal energy and applications to mononucleotide repeat DNA, J. Biomol. Struct. Dyn, vol.3, pp.989-1014, 1986.
URL : https://hal.archives-ouvertes.fr/hal-00313463

A. Blondel, J. P. Renaud, S. Fischer, D. Moras, and M. Karplus, Retinoic acid receptor: a simulation analysis of retinoic acid binding and the resulting conformational changes, J. Mol. Biol, vol.291, pp.101-115, 1999.

E. Laine, C. Goncalves, J. Karst, A. Lesnard, S. Rault et al., Use of allostery to identify inhibitors of calmodulin-induced activation of Bacillus anthracis Edema Factor, Proc. Natl. Acad. Sci. U.S.A, vol.107, pp.11277-11282, 2010.
URL : https://hal.archives-ouvertes.fr/pasteur-01501815

S. Miyamoto and P. A. Kollman, Absolute and relative binding free energy calculations of the interaction of biotin and its analogs with streptavidin using molecular dynamics/free energy perturbation approaches, Proteins, vol.16, pp.226-245, 1993.

H. Gouda, I. D. Kuntz, D. A. Case, and P. A. Kollman, Free energy calculations for theophylline binding to an RNA aptamer: Comparison of MM-PBSA and thermodynamic integration methods, Biopolymers, vol.68, pp.16-34, 2003.

T. Steinbrecher, D. A. Case, and A. Labahn, A multistep approach to structurebased drug design: studying ligand binding at the human neutrophil elastase, J. Med. Chem, vol.49, pp.1837-1844, 2006.

J. G. Kirkwood, Statistical mechanics of fluid mixtures, J. Chem. Phys, vol.3, pp.300-313, 1935.

D. A. Case, T. A. Darden, T. E. Cheatham, C. L. Simmerling, J. Wang et al., , 2008.

A. Blondel, Ensemble variance in free energy calculations by thermodynamic integration: theory, optimal Alchemical path, and practical solutions, J Comput Chem, vol.25, pp.985-993, 2004.

J. P. Ryckaert, G. Ciccotti, and H. J. Berendsen, Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes, 1977.

, J Comput Phys, vol.23, pp.327-341

J. Wang, Y. Deng, and B. Roux, Absolute binding free energy calculations using molecular dynamics simulations with restraining potentials, Biophys. J, vol.91, pp.2798-2814, 2006.

T. P. Straatsma, H. J. Berendsen, and A. J. Stam, Estimation of statistical errors in molecular simulation calculations, Mol. Phys, vol.57, pp.89-95, 1986.

Z. Grabarek, Structure of a trapped intermediate of calmodulin: calcium regulation of EF-hand proteins from a new perspective, J. Mol. Biol, vol.346, pp.1351-66, 2005.

R. Elber and M. Karplus, Enhanced sampling in molecular dynamics: Use of the Time-Dependent Hartree approximation for a simulation of carbon monoxide diffusion through myoglobin, J. Am. Chem. Soc, vol.112, pp.9161-9175, 1990.

A. Ulitsky and R. Elber, The thermal equilibrium aspects of the time dependent Hartree and the locally enhanced sampling approximations: formal properties, a correction, and computational examples for rare gas clusters, J. Chem. Phys, vol.98, pp.3380-3388, 1993.

Y. Deng and B. Roux, Computations of standard binding free energies with molecular dynamics simulations, J Phys Chem B, vol.113, pp.2234-2246, 2009.

T. Steinbrecher, A. Hrenn, K. L. Dormann, I. Merfort, and A. Labahn, Bornyl (3,4,5-trihydroxy)-cinnamate-an optimized human neutrophil elastase inhibitor designed by free energy calculations, Bioorg. Med. Chem, vol.16, pp.2385-2390, 2008.

H. Yu, T. W. Whitfield, E. Harder, G. Lamoureux, I. Vorobyov et al., Simulating monovalent and divalent ions in aqueous solution using a drude polarizable force field, Article ASAP, 2010.

J. T. Warren, Q. Guo, and W. J. Tang, A 1.3-Å structure of zinc-bound N-terminal domain of calmodulin elucidates potential early ion-binding step, J. Mol. Biol, vol.374, pp.517-527, 2007.
URL : https://hal.archives-ouvertes.fr/hal-00426282

C. Kobayashi and S. Takada, Protein grabs a ligand by extending anchor residues: molecular simulation for Ca 2+ binding to calmodulin loop, Biophys. J, vol.90, pp.3043-3051, 2006.

Y. Zhang, H. Tan, Y. Lu, Z. Jia, C. et al., Ca 2+ dissociation from the C-terminal EF-hand pair in calmodulin: a steered molecular dynamics study, FEBS Lett, vol.582, pp.1355-1361, 2008.

J. E. Debreczeni, L. Farkas, V. Harmat, C. Het?yi, I. Hajdú et al., Structural evidence for non-canonical binding of Ca2+ to a canonical EF-hand of a conventional myosin, J. Biol. Chem, vol.280, pp.41458-41464, 2005.

E. Laine, A. Blondel, and T. E. Malliavin, Dynamics and energetics: a consensus analysis of the impact of calcium on EF-CaM protein complex, Biophys. J, vol.96, pp.1249-1263, 2009.

C. Yang, G. S. Jas, and K. Kuczera, Structure, dynamics and interaction with kinase targets: computer simulations of calmodulin, Biochim. Biophys. Acta, vol.1697, pp.289-300, 2004.

, S1 ( ? ) S2 ( ? ) S3 ( ? ) S4 ( ? )

, and S4, and solvent accessible surface area (SASA) inÅ 2 of CaM N-terminal and C-terminal hydrophobic patches, as defined by Yang et al. (56). Values are given for the crystallographic structures 1K93 of EF-(2Ca-CaM) and 1XFX of EF-(4Ca-CaM) and for the MD trajectories of 1k93-4Ca and 1xfx-4Ca, Table I: Average inter-helical angles ( ? ) of CaM S1, S2

, Number of oxygens in the calcium coordination spheres of S1, S2, S3 and S4, with 2 oxygens displayed in white, 3 oxygens in yellow, 4 oxygens in orange, 5 oxygens in red and 6 oxygens in purple; (c-d,f-g) Coordination distances in calcium binding sites (c) S1 of 1k93-4Ca, (d) S2 of 1k93-4Ca, (f) S1 of 1xfx-4Ca, (g) S2 of 1xfx-4Ca, CaM atomic fluctuations per residue over the 12 last nanoseconds of 1k93-2Ca (16) (black dashed line and crosses), 1k93-4Ca (black solid line and circles) and 1xfx-4Ca (gray solid line and circles) MD trajectories, and schematics secondary structure. (b-g) Calcium coordination in (b-d) 1k93-4Ca and (e-g) 1xfx-4Ca trajectories respectively: (b,e), pp.1-5