J. D. Westbrook and S. K. Burley, How structural biologists and the protein data bank contributed to recent FDA new drug approvals, 2018.

K. Henzler-wildman and D. Kern, Dynamic personalities of proteins, Nature, vol.450, pp.964-972, 2007.

H. Arthanari, K. Takeuchi, A. Dubey, and G. Wagner, Emerging solution NMR methods to illuminate the structural and dynamic properties of proteins, Curr. Opin. Struct. Biol, 2019.

T. J. Harpole and L. Delemotte, Conformational landscapes of membrane proteins delineated by enhanced sampling molecular dynamics simulations, Biochim. Biophys. Acta, p.33, 1860.

K. Goossens and H. De-winter, Molecular dynamics simulations of membrane proteins: an overview, J. Chem. Inf. Model, vol.58, pp.2193-2202, 2018.

M. A. Damgen and P. C. Biggin, Computational methods to examine conformational changes and ligand-binding properties: examples in neurobiology, Neurosci. Lett, 2018.

M. Bonomi, G. T. Heller, C. Camilloni, and M. Vendruscolo, Principles of protein structural ensemble determination, Curr. Opin. Struct. Biol, vol.42, pp.106-116, 2017.

K. Lindorff-larsen, P. Maragakis, S. Piana, and D. E. Shaw, Picosecond to millisecond structural dynamics in human ubiquitin, J. Phys. Chem. B, vol.120, pp.8313-8320, 2016.

D. E. Shaw, Atomic-level characterization of the structural dynamics of proteins, Science, vol.330, pp.341-346, 2010.

K. J. Kohlhoff, Cloud-based simulations on google exacycle reveal ligand modulation of GPCR activation pathways, Nature chemistry, vol.6, pp.15-21, 2014.

G. Martinez-rosell, T. Giorgino, M. J. Harvey, and G. De-fabritiis, Drug discovery and molecular dynamics: methods, applications and perspective beyond the second timescale, Curr. Top. Med. Chem, vol.17, p.42549, 2017.

, Scientific RepoRtS |, vol.10, p.15901, 2020.

A. Kapoor, G. Martinez-rosell, D. Provasi, G. De-fabritiis, and M. Filizola, Dynamic and kinetic elements of micro-opioid receptor functional selectivity, 2017.

U. Doshi and D. Hamelberg, Towards fast, rigorous and efficient conformational sampling of biomolecules: advances in accelerated molecular dynamics, Biochem. Biophys. Acta, pp.878-888, 1850.

P. C. Gedeon, J. R. Thomas, and J. D. Madura, Accelerated molecular dynamics and protein conformational change: a theoretical and practical guide using a membrane embedded model neurotransmitter transporter, Methods Mol. Biol, vol.1215, pp.253-287, 2015.

M. J. Capper and D. Wacker, How the ubiquitous GPCR receptor family selectively activates signalling pathways, Nature, vol.558, pp.529-530, 2018.

X. E. Zhou, K. Melcher, and H. E. Xu, Understanding the GPCR biased signaling through G protein and arrestin complex structures, Curr. Opin. Struct. Biol, vol.45, pp.150-159, 2017.

Y. Kang, Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser, Nature, vol.523, pp.561-567, 2015.

S. G. Rasmussen, Crystal structure of the beta2 adrenergic receptor-Gs protein complex, Nature, vol.477, pp.549-555, 2011.

R. Nygaard, T. M. Frimurer, B. Holst, M. M. Rosenkilde, and T. W. Schwartz, Ligand binding and micro-switches in 7TM receptor structures, Trends Pharmacol. Sci, vol.30, pp.249-259, 2009.

A. J. Venkatakrishnan, Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region, Nature, vol.536, pp.484-487, 2016.
URL : https://hal.archives-ouvertes.fr/hal-02448488

A. J. Venkatakrishnan, Molecular signatures of G-protein-coupled receptors, Nature, vol.494, pp.185-194, 2013.
URL : https://hal.archives-ouvertes.fr/hal-02448448

A. J. Venkatakrishnan, Diverse GPCRs exhibit conserved water networks for stabilization and activation, Proc. Natl. Acad. Sci. USA, vol.116, pp.3288-3293, 2019.

N. R. Latorraca, A. J. Venkatakrishnan, and R. O. Dror, GPCR dynamics: structures in motion, Chem. Rev, vol.117, p.77, 2017.

D. Hilger, M. Masureel, and B. K. Kobilka, Structure and dynamics of GPCR signaling complexes, Nat. Struct. Mol. Biol, vol.25, pp.4-12, 2018.

R. O. Dror, Activation mechanism of the beta2-adrenergic receptor, Proc. Natl. Acad. Sci. USA, vol.108, pp.18684-18689, 2011.

D. Provasi and M. Filizola, Putative active states of a prototypic g-protein-coupled receptor from biased molecular dynamics, Biophys. J, vol.98, pp.2347-2355, 2010.

Y. Miao, S. E. Nichols, P. M. Gasper, V. T. Metzger, and J. A. Mccammon, Activation and dynamic network of the M2 muscarinic receptor, Proc. Natl. Acad. Sci. USA, vol.110, pp.10982-10987, 2013.

Y. Miao, A. D. Caliman, and J. A. Mccammon, Allosteric effects of sodium ion binding on activation of the m3 muscarinic g-proteincoupled receptor, Biophys. J, vol.108, pp.1796-1806, 2015.

I. G. Tikhonova, B. Selvam, A. Ivetac, J. Wereszczynski, and J. A. Mccammon, Simulations of biased agonists in the beta(2) adrenergic receptor with accelerated molecular dynamics, Biochemistry, vol.52, pp.5593-5603, 2013.

B. J. Killian, Configurational entropy in protein-peptide binding: computational study of Tsg101 ubiquitin E2 variant domain with an HIV-derived PTAP nonapeptide, J. Mol. Biol, vol.389, pp.315-335, 2009.

N. Vaidehi and A. Jain, Internal coordinate molecular dynamics: a foundation for multiscale dynamics, J. Phys. Chem. B, vol.119, pp.1233-1242, 2015.

S. C. Sealfon, Related contribution of specific helix 2 and 7 residues to conformational activation of the serotonin 5-HT2A receptor, J. Biol. Chem, vol.270, pp.16683-16688, 1995.

B. Taddese, Evolution of chemokine receptors is driven by mutations in the sodium binding site, PLoS Comput. Biol, vol.14, p.9, 2018.
URL : https://hal.archives-ouvertes.fr/inserm-02145753

B. Wu, Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists, Science, vol.330, p.96, 2010.

G. Fenalti, Molecular control of delta-opioid receptor signalling, Nature, vol.506, pp.191-196, 2014.

S. Jo, CHARMM-GUI 10 years for biomolecular modeling and simulation, J. Comput. Chem, vol.38, pp.1114-1124, 2017.

J. C. Phillips, Scalable molecular dynamics with NAMD, J. Comput. Chem, vol.26, pp.1781-1802, 2005.

R. B. Best, Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone phi, psi and side-chain chi(1) and chi(2) dihedral angles, J. Chem. Theory Comput, vol.8, pp.3257-3273, 2012.

J. B. Klauda, Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types, J. Phys. Chem. B, vol.114, pp.7830-7843, 2010.

M. Daydé, E-Biothon: an experimental platform for BioInformatics, Proceedings of International Conference on Computer Science and Information Technologies, pp.1-4, 2015.

Y. Wang, C. B. Harrison, K. Schulten, and J. A. Mccammon, Implementation of accelerated molecular dynamics in NAMD, Comput. Sci. Discov, 2011.

B. J. Grant, A. P. Rodrigues, K. M. Elsawy, J. A. Mccammon, and L. S. Caves, Bio3d: an R package for the comparative analysis of protein structures, Bioinformatics, vol.22, issue.1, pp.2695-2696, 2006.

W. Humphrey, A. Dalke, and K. Schulten, VMD: visual molecular dynamics, J. Mol. Graph, vol.14, pp.27-38, 1996.

C. L. Towse, S. J. Rysavy, I. M. Vulovic, and V. Daggett, New dynamic rotamer libraries: data-driven analysis of side-chain conformational propensities, Structure, vol.24, pp.187-199, 2016.

N. I. Fisher and A. J. Lee, A correlation-coefficient for circular data, Biometrika, vol.70, pp.327-332, 1983.

S. R. Jammalamadaka and A. Sengupta, Circular Statistics, 2001.

C. Agostinelli, U. Lund, and . Package-'circular, Circular Statistics, 2017.

A. A. Fodor and R. W. Aldrich, Influence of conservation on calculations of amino acid covariance in multiple sequence alignments, Proteins, vol.56, pp.211-221, 2004.

A. A. Fodor and R. W. Aldrich, On evolutionary conservation of thermodynamic coupling in proteins, J. Biol. Chem, vol.279, pp.19046-19050, 2004.

J. Pele, Comparative analysis of sequence covariation methods to mine evolutionary hubs: examples from selected GPCR families, Proteins, vol.82, pp.2141-2156, 2014.
URL : https://hal.archives-ouvertes.fr/hal-02281524

H. Abdi, Encyclopedia of Measurement and Statistics, pp.1057-1058, 2007.

G. Su, J. H. Morris, B. Demchak, and G. D. Bader, Biological network exploration with Cytoscape 3, Curr. Protoc. Bioinform, vol.47, pp.11-24, 2014.

H. Abdi and L. J. Williams, Principal component analysis, Wiley Interdiscip. Rev, vol.2, pp.433-459, 2010.
URL : https://hal.archives-ouvertes.fr/hal-01259094

, Scientific RepoRtS |, vol.10, p.15901, 2020.

R. L. Dunbrack and M. Karplus, Conformational analysis of the backbone-dependent rotamer preferences of protein sidechains, Nat. Struct. Biol, vol.1, pp.334-340, 1994.

S. L. Scherer, A. L. Stewart, and R. C. Fortenberry, Patterns of cation binding to the aromatic amino acid R groups in Trp, Tyr, and Phe, Comput. Biol. Chem, vol.72, pp.11-15, 2018.

M. P. Wescott, Signal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices, Proc. Natl. Acad. Sci. USA, vol.113, pp.9928-9933, 2016.

Y. Shang, Mechanistic insights into the allosteric modulation of opioid receptors by sodium ions, Biochemistry, vol.53, pp.5140-5149, 2014.

O. N. Vickery, Intracellular transfer of Na(+) in an active-state G-protein-coupled receptor, Structure, vol.26, pp.171-180, 2018.

S. Yuan, H. Vogel, and S. Filipek, The role of water and sodium ions in the activation of the mu-opioid receptor, Angew. Chem, vol.52, pp.10112-10115, 2013.

G. A. Tribello and P. Gasparotto, Using data-reduction techniques to analyze biomolecular trajectories, Methods Mol. Biol, pp.453-502, 2019.

M. A. Rohrdanz, W. Zheng, and C. Clementi, Discovering mountain passes via torchlight: methods for the definition of reaction coordinates and pathways in complex macromolecular reactions, Annu. Rev. Phys. Chem, vol.64, pp.295-316, 2013.

M. Ernst, F. Sittel, and G. Stock, Contact-and distance-based principal component analysis of protein dynamics, J. Chem. Phys, vol.143, p.244114, 2015.

F. Sittel, A. Jain, and G. Stock, Principal component analysis of molecular dynamics: on the use of Cartesian vs. internal coordinates, J. Chem. Phys, vol.141, p.14111, 2014.

F. Sittel and G. Stock, Perspective: Identification of collective variables and metastable states of protein dynamics, J. Chem. Phys, vol.149, p.150901, 2018.

W. B. Zhang, A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C are weak partial agonists, J. Biol. Chem, vol.277, pp.24515-24521, 2002.

H. Zhang, Structure of the Angiotensin receptor revealed by serial femtosecond crystallography, Cell, vol.161, pp.833-844, 2015.

C. Zhang, High-resolution crystal structure of human protease-activated receptor 1, Nature, vol.492, pp.387-392, 2012.

V. Katritch, Allosteric sodium in class A GPCR signaling, Trends Biochem. Sci, vol.39, pp.233-244, 2014.

B. Zarzycka, S. A. Zaidi, B. L. Roth, and V. Katritch, Harnessing Ion-Binding sites for GPCR pharmacology, Pharmacol. Rev, vol.71, pp.571-595, 2019.

A. Koehl, Structure of the micro-opioid receptor-Gi protein complex, Nature, vol.558, pp.547-552, 2018.
URL : https://hal.archives-ouvertes.fr/hal-02071092

L. M. Wingler, Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR, Science, vol.367, pp.888-892, 2020.

H. Asada, Crystal structure of the human angiotensin II type 2 receptor bound to an angiotensin II analog, Nat. Struct. Mol. Biol, vol.25, pp.570-576, 2018.

H. Zhang, Structural basis for selectivity and diversity in angiotensin II receptors, Nature, vol.544, pp.327-332, 2017.

C. M. Suomivuori, Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor, Science, vol.367, pp.881-887, 2020.

Y. X. Tao, A. N. Abell, X. Liu, K. Nakamura, and D. L. Segaloff, Constitutive activation of G protein-coupled receptors as a result of selective substitution of a conserved leucine residue in transmembrane helix III, Mol. Endocrinol, vol.14, pp.1272-1282, 2000.

B. Trzaskowski, Action of molecular switches in GPCRs-theoretical and experimental studies, Curr. Med. Chem, vol.19, pp.99320-556, 2012.

T. Costa, J. Lang, C. Gless, and A. Herz, Spontaneous association between opioid receptors and GTP-binding regulatory proteins in native membranes: specific regulation by antagonists and sodium ions, Mol. Pharmacol, vol.37, pp.383-394, 1990.

D. E. Selley, C. C. Cao, Q. Liu, and S. R. Childers, Effects of sodium on agonist efficacy for G-protein activation in mu-opioid receptor-transfected CHO cells and rat thalamus, Br. J. Pharmacol, vol.130, pp.987-996, 2000.

J. M. Janz, Direct interaction between an allosteric agonist pepducin and the chemokine receptor CXCR4, J. Am. Chem. Soc, vol.133, pp.15878-15881, 2011.

J. Quoyer, Pepducin targeting the C-X-C chemokine receptor type 4 acts as a biased agonist favoring activation of the inhibitory G protein, Proc. Natl. Acad. Sci. USA, vol.110, pp.5088-5097, 2013.

E. Papaleo, Integrating atomistic molecular dynamics simulations, experiments, and network analysis to study protein dynamics: strength in unity. Front, Mol. Biosci, vol.2, 2015.

L. Vuillon and C. Lesieur, From local to global changes in proteins: a network view, Curr. Opin. Struct. Biol, vol.31, pp.1-8, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01921161

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