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Influence of orthosteric ligand binding on the conformational dynamics of the β-2-adrenergic receptor via essential dynamics sampling simulation

  • Structural and Functional Analysis of Biopolymers and Biopolymer Complexes
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Abstract

The influence of the binding of orthosteric ligands on the conformational dynamics of the β-2-adrenoreceptor was identified using the molecular dynamics method. It was found that there was a small fraction of active states of the receptor in its apo (ligand free) ensemble. An analysis of the MD trajectories indicated that this spontaneous activation of the receptor was accompanied by the motion of its VI helix. Thus, the receptor’s constitutive activity is a direct result of its conformational dynamics. On the other hand, the binding of the full agonist resulted in a significant shift in the initial equilibrium towards its active state. Finally, the binding of the inverse agonist stabilized receptor in its inactive state. It is likely that the binding of the inverse agonists might be a universal method of the constitutive activity inhibition. Our results indicate that ligand binding redistributes preexisting conformational degrees of freedom (in accordance to the Monod-Wyman-Changeux Model), rather than causes an induced fit. Therefore, the ensemble of the biologically relevant receptors conformations has been encoded in its spatial structure and individual conformations from that ensemble and might be used by the cell according to the physiological behavior.

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Abbreviations

MD:

molecular dynamics

EDS:

essential dynamics sampling

GPCR:

G-protein coupled receptors

7-TM:

7-transmembrane

B2AR:

β-2-adrenoreceptor

TMD:

transmembrane domain

PDB:

protein data bank

SD:

standard deviation

PCA:

principal componential analysis

PC:

principal component

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Authors and Affiliations

  1. Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia

    G. V. Novikov & V. S. Sivozhelezov

  2. Department of Biology, Moscow State University, Moscow, 119991, Russia

    K. V. Shaitan

Authors
  1. G. V. Novikov
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  2. V. S. Sivozhelezov
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  3. K. V. Shaitan
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Correspondence to G. V. Novikov.

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Original Russian Text © G.V. Novikov, V.S. Sivozhelezov, K.V. Shaitan, 2014, published in Molekulyarnaya Biologiya, 2014, Vol. 48, No. 3, pp. 463–479.

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Novikov, G.V., Sivozhelezov, V.S. & Shaitan, K.V. Influence of orthosteric ligand binding on the conformational dynamics of the β-2-adrenergic receptor via essential dynamics sampling simulation. Mol Biol 48, 399–413 (2014). https://doi.org/10.1134/S0026893314030157

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  • DOI: https://doi.org/10.1134/S0026893314030157

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