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Communication over the network of binary switches regulates the activation of A2A adenosine receptor.

Lee Y, Choi S, Hyeon C - PLoS Comput. Biol. (2015)

Bottom Line: We dubbed these 10 structural motifs "binary switches" as they display molecular interactions that switch between two distinct states.By projecting the receptor dynamics on these binary switches that yield 2(10) microstates, we show that (i) the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space; (ii) among the three receptor states the apo state explores the broadest range of microstates; (iii) in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches; and (iv) to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor activation.Finally, our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif.

View Article: PubMed Central - PubMed

Affiliation: National Leading Research Laboratory (NLRL) of Molecular Modeling and Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Korea.

ABSTRACT
Dynamics and functions of G-protein coupled receptors (GPCRs) are accurately regulated by the type of ligands that bind to the orthosteric or allosteric binding sites. To glean the structural and dynamical origin of ligand-dependent modulation of GPCR activity, we performed total ~ 5 μsec molecular dynamics simulations of A2A adenosine receptor (A2AAR) in its apo, antagonist-bound, and agonist-bound forms in an explicit water and membrane environment, and examined the corresponding dynamics and correlation between the 10 key structural motifs that serve as the allosteric hotspots in intramolecular signaling network. We dubbed these 10 structural motifs "binary switches" as they display molecular interactions that switch between two distinct states. By projecting the receptor dynamics on these binary switches that yield 2(10) microstates, we show that (i) the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space; (ii) among the three receptor states the apo state explores the broadest range of microstates; (iii) in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches; and (iv) to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor activation. Finally, our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif.

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Dynamics of A2AAR in 10-binary switch representation.(a) Simulation trajectories of antagonist (blue), apo (black), agonist (red) form represented in terms of the ON/OFF state of 10 switches. The lines denote the ON states, and the trajectories evolve from the top to bottom. (b) Mean value of each switch with error bar denoting the standard deviation. (c) Time traces of the microstates represented by the decimal numbers from 0 to 1023 in the apo (black), antagonist-bound (blue), and agonist-bound (red) forms. (d) Corresponding population of the microstates. (e) A schematic of similarity between three receptor states in terms of Hamming distance dαβ with the measure of complexity, I (Eq. 2), illustrated with polygons.
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pcbi.1004044.g005: Dynamics of A2AAR in 10-binary switch representation.(a) Simulation trajectories of antagonist (blue), apo (black), agonist (red) form represented in terms of the ON/OFF state of 10 switches. The lines denote the ON states, and the trajectories evolve from the top to bottom. (b) Mean value of each switch with error bar denoting the standard deviation. (c) Time traces of the microstates represented by the decimal numbers from 0 to 1023 in the apo (black), antagonist-bound (blue), and agonist-bound (red) forms. (d) Corresponding population of the microstates. (e) A schematic of similarity between three receptor states in terms of Hamming distance dαβ with the measure of complexity, I (Eq. 2), illustrated with polygons.

Mentions: Representing GPCR conformation in terms of the 10 binary switches amounts to “choosing” multiple progress coordinates (or multi-dimensional order parameters) to probe the allosteric dynamics of GPCR from the inactive to active state. The assumption that 10 binary switch can faithfully represent the dynamics of GPCRs leads to in total, 210 possible microstates; each microstate is expressed using binary number from 0000000000(2) to 1111111111(2) with each digit denoting the switch number from 1 to 10. These binary numbers can also be expressed with a decimal number from 0 and 1023 (Fig. S6). The time traces projected on the 10 binary switches and 210 microstates are shown in Fig. 5a and Fig. 5c, respectively. The average value of each switch, calculated in different receptor state ξ as 0 ≤ ⟨sξ,i⟩ ≤ 1 (Fig. 5b), where ⟨sξ,i⟩ with i denoting the switch index is the value of switch averaged over the simulation time, indicates that on average switches are ON in the agonist-bound form, OFF in the antagonist-bound form, and they lie in between in the apo form. The difference among the three receptor forms becomes more evident in terms of the population of microstates (Fig. 5d). The statistics of microstates shows that the receptor occupies different population of microstates depending on the type of ligand (Fig. 5). Among the entire microstates as summarized in Fig. 6, (i) ≈ 80% of antagonist-bound form are populated in the 0000000000 or 0000000001 state. (ii) ≈ 20.2% of the switches in the agonist-bound form are in 1023th state (1111111111(2)), and ≈ 31.28% are in 895th state (1101111111(2)). (iii) Lastly, in the apo form of GPCR, on an average, , , are ON state, while , , , , are OFF state. Microstates that constitute the major population of the apo form are 1000000101(2) (31.32%) and 1001000101(2) (10.56%).


Communication over the network of binary switches regulates the activation of A2A adenosine receptor.

Lee Y, Choi S, Hyeon C - PLoS Comput. Biol. (2015)

Dynamics of A2AAR in 10-binary switch representation.(a) Simulation trajectories of antagonist (blue), apo (black), agonist (red) form represented in terms of the ON/OFF state of 10 switches. The lines denote the ON states, and the trajectories evolve from the top to bottom. (b) Mean value of each switch with error bar denoting the standard deviation. (c) Time traces of the microstates represented by the decimal numbers from 0 to 1023 in the apo (black), antagonist-bound (blue), and agonist-bound (red) forms. (d) Corresponding population of the microstates. (e) A schematic of similarity between three receptor states in terms of Hamming distance dαβ with the measure of complexity, I (Eq. 2), illustrated with polygons.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4322061&req=5

pcbi.1004044.g005: Dynamics of A2AAR in 10-binary switch representation.(a) Simulation trajectories of antagonist (blue), apo (black), agonist (red) form represented in terms of the ON/OFF state of 10 switches. The lines denote the ON states, and the trajectories evolve from the top to bottom. (b) Mean value of each switch with error bar denoting the standard deviation. (c) Time traces of the microstates represented by the decimal numbers from 0 to 1023 in the apo (black), antagonist-bound (blue), and agonist-bound (red) forms. (d) Corresponding population of the microstates. (e) A schematic of similarity between three receptor states in terms of Hamming distance dαβ with the measure of complexity, I (Eq. 2), illustrated with polygons.
Mentions: Representing GPCR conformation in terms of the 10 binary switches amounts to “choosing” multiple progress coordinates (or multi-dimensional order parameters) to probe the allosteric dynamics of GPCR from the inactive to active state. The assumption that 10 binary switch can faithfully represent the dynamics of GPCRs leads to in total, 210 possible microstates; each microstate is expressed using binary number from 0000000000(2) to 1111111111(2) with each digit denoting the switch number from 1 to 10. These binary numbers can also be expressed with a decimal number from 0 and 1023 (Fig. S6). The time traces projected on the 10 binary switches and 210 microstates are shown in Fig. 5a and Fig. 5c, respectively. The average value of each switch, calculated in different receptor state ξ as 0 ≤ ⟨sξ,i⟩ ≤ 1 (Fig. 5b), where ⟨sξ,i⟩ with i denoting the switch index is the value of switch averaged over the simulation time, indicates that on average switches are ON in the agonist-bound form, OFF in the antagonist-bound form, and they lie in between in the apo form. The difference among the three receptor forms becomes more evident in terms of the population of microstates (Fig. 5d). The statistics of microstates shows that the receptor occupies different population of microstates depending on the type of ligand (Fig. 5). Among the entire microstates as summarized in Fig. 6, (i) ≈ 80% of antagonist-bound form are populated in the 0000000000 or 0000000001 state. (ii) ≈ 20.2% of the switches in the agonist-bound form are in 1023th state (1111111111(2)), and ≈ 31.28% are in 895th state (1101111111(2)). (iii) Lastly, in the apo form of GPCR, on an average, , , are ON state, while , , , , are OFF state. Microstates that constitute the major population of the apo form are 1000000101(2) (31.32%) and 1001000101(2) (10.56%).

Bottom Line: We dubbed these 10 structural motifs "binary switches" as they display molecular interactions that switch between two distinct states.By projecting the receptor dynamics on these binary switches that yield 2(10) microstates, we show that (i) the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space; (ii) among the three receptor states the apo state explores the broadest range of microstates; (iii) in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches; and (iv) to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor activation.Finally, our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif.

View Article: PubMed Central - PubMed

Affiliation: National Leading Research Laboratory (NLRL) of Molecular Modeling and Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Korea.

ABSTRACT
Dynamics and functions of G-protein coupled receptors (GPCRs) are accurately regulated by the type of ligands that bind to the orthosteric or allosteric binding sites. To glean the structural and dynamical origin of ligand-dependent modulation of GPCR activity, we performed total ~ 5 μsec molecular dynamics simulations of A2A adenosine receptor (A2AAR) in its apo, antagonist-bound, and agonist-bound forms in an explicit water and membrane environment, and examined the corresponding dynamics and correlation between the 10 key structural motifs that serve as the allosteric hotspots in intramolecular signaling network. We dubbed these 10 structural motifs "binary switches" as they display molecular interactions that switch between two distinct states. By projecting the receptor dynamics on these binary switches that yield 2(10) microstates, we show that (i) the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space; (ii) among the three receptor states the apo state explores the broadest range of microstates; (iii) in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches; and (iv) to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor activation. Finally, our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif.

Show MeSH
Related in: MedlinePlus