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PreprintCited by 10Receptor Mechanisms and SignalingBiochemical Analysis and Sensing TechniquesProtein Structure and Dynamics

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Exploring TAS2R46 Biomechanics through Molecular Dynamics and Network Analysis

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Cannariato, Marco, Fanunza, Riccardo, Zizzi, Eric A., Miceli, Marcello, Di Benedetto, Giacomo, Deriu, Marco A., Pallante, Lorenzo·2023·Frontiers in Molecular Biosciences
DOI 10.1101/2023.11.21.568072PMC PMC11646861

Preprint — published as 10.3389/fmolb.2024.1473675

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Abstract

Understanding the intricate interplay between structural features and signal-processing events is crucial for unravelling the mechanisms of biomolecular systems. G protein-coupled receptors (GPCRs), a pervasive protein family in humans, serve a wide spectrum of vital functions. TAS2Rs, a subfamily of GPCRs, play a primary role in recognizing bitter molecules and triggering events leading to the perception of bitterness, a crucial defence mechanism against spoiled or poisonous food. Beyond taste, TAS2Rs function is associated with many diseases as they are expressed in several extra-oral tissues. Since the precise mechanism of TAS2R activation is poorly understood, this work aims to characterize the mechanisms underlying the signal transduction on the recently experimentally solved human TAS2R46 bitter taste receptor using molecular dynamics simulations coupled with network-based analysis. The results show that the allosteric activation of the receptor is associated with more correlated dynamics of the receptor and the formation of an interaction between two helices which mainly convey the signal transferring from the extracellular to the intracellular region. By elucidating the hallmarks of the allosteric network of TAS2R46 under varying conditions (ligand-bound, ligand-free, and transition states), this study has enabled the identification of the unique functional mechanisms of this receptor, thereby establishing a foundation for a more profound characterisation of this intriguing class of receptors. Highlights: The dynamics of TAS2R46 in different states were studied through molecular dynamics and network analysis. The presence of the bitter agonist increases intra-protein correlations. TM3 and TM6 helices mediate the allosteric network in Holo TAS2R46. The rotation of Y241 6.48 residue is pivotal in the allosteric network for the Holo TAS2R46.

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Figures

FIGURE 1 Visual representation of the Holo, Trans and Apo systems. The 7 TMs of TAS2R46 are highlighted with different colours, the hydrophobic tails and hydrophilic head of POPC are coloured in light green and red, respectively.
FIGURE 1 Visual representation of the Holo, Trans and Apo systems. The 7 TMs of TAS2R46 are highlighted with different colours, the hydrophobic tails and hydrophilic head of POPC are coloured in light green and red, respectively.CC BY · PubMed Central
FIGURE 2 Conformational analysis of TAS2R46 in the three investigated states. (A) Probability distribution of the dihedral angle (defined by the atoms CA-CB-CG-CD1) of residue Y2416.48. Orange and blue dashed lines indicate the dihedral angles observed in the experimental structures of the Holo (PDB: 7XP6) and Apo states (PDB: 7XP4), respectively. (B) Probability distribution of minimal distances of Y2416.48 from residues T2747.48 (left) and N923.36 (right). (C) Rendering of representative structures of the three receptor states, highlighting the relative positions of residues Y2416.48 (white), T2747.48 (red) and N923.36 (pink). Hydrogen bonds are depicted as black dotted lines. The Holo structure is shown in orange, Trans in green, and Apo in blue.
FIGURE 2 Conformational analysis of TAS2R46 in the three investigated states. (A) Probability distribution of the dihedral angle (defined by the atoms CA-CB-CG-CD1) of residue Y2416.48. Orange and blue dashed lines indicate the dihedral angles observed in the experimental structures of the Holo (PDB: 7XP6) and Apo states (PDB: 7XP4), respectively. (B) Probability distribution of minimal distances of Y2416.48 from residues T2747.48 (left) and N923.36 (right). (C) Rendering of representative structures of the three receptor states, highlighting the relative positions of residues Y2416.48 (white), T2747.48 (red) and N923.36 (pink). Hydrogen bonds are depicted as black dotted lines. The Holo structure is shown in orange, Trans in green, and Apo in blue.CC BY · PubMed Central
FIGURE 3 (A) Visual representation of the binding pocket volume (in red) of TAS2R46 for one selected frame of the Apo system. (B) Probability distribution of the binding pocket volume for the Holo, Trans, and Apo states, represented in orange, green and blue, respectively. The ECL2, not shown in this representation, was excluded from the calculation of the binding pocket volume to prevent any alterations in the estimation, as it is located within the investigated pocket in the Apo state.
FIGURE 3 (A) Visual representation of the binding pocket volume (in red) of TAS2R46 for one selected frame of the Apo system. (B) Probability distribution of the binding pocket volume for the Holo, Trans, and Apo states, represented in orange, green and blue, respectively. The ECL2, not shown in this representation, was excluded from the calculation of the binding pocket volume to prevent any alterations in the estimation, as it is located within the investigated pocket in the Apo state.CC BY · PubMed Central
FIGURE 4 Matrices showing the generalized correlation coefficient between the residues of TAS2R46 in the (A) Holo, (B) Trans, and (C) Apo states. In panel (D), the differences of the generalized correlation coefficients are shown: ΔrMI(Trans, Holo) = rMI(Trans) - rMI(Holo) in the lower triangle and ΔrMI(Apo, Holo) = rMI(Apo) - rMI(Holo) in the upper triangle. Matrices on panels from (A to B) are coloured according to the left colorbar, while the matrix on panel (D) is colored according to the right colorbar.
FIGURE 4 Matrices showing the generalized correlation coefficient between the residues of TAS2R46 in the (A) Holo, (B) Trans, and (C) Apo states. In panel (D), the differences of the generalized correlation coefficients are shown: ΔrMI(Trans, Holo) = rMI(Trans) - rMI(Holo) in the lower triangle and ΔrMI(Apo, Holo) = rMI(Apo) - rMI(Holo) in the upper triangle. Matrices on panels from (A to B) are coloured according to the left colorbar, while the matrix on panel (D) is colored according to the right colorbar.CC BY · PubMed Central
FIGURE 5 Dynamical Network Analysis of the Holo, Trans, and Apo systems. (A) Boxplots representing the distribution of node betweenness centrality, with nodes grouped into the respective TMs. Data emphasize that in the absence of the ligand TM3 assumed a primary role in information transfer, whereas in the presence of strychnine TM6 nodes also demonstrated high values of betweenness centrality. (B) Eigenvector centrality of TAS2R46 nodes. The TMs and loops are highlighted as well as residues pinpointed in previous experimental analysis. Results showed higher centrality of TM6 with strychnine, especially for H2055.68, H2246.31, and Y2416.48, and decreased centralities in the Trans state. (C) Visual representation of the dynamic networks, where the receptor is viewed from the IC region. The edges of the network are red cylinders with a radius proportional to the betweenness centrality of the edge.
FIGURE 5 Dynamical Network Analysis of the Holo, Trans, and Apo systems. (A) Boxplots representing the distribution of node betweenness centrality, with nodes grouped into the respective TMs. Data emphasize that in the absence of the ligand TM3 assumed a primary role in information transfer, whereas in the presence of strychnine TM6 nodes also demonstrated high values of betweenness centrality. (B) Eigenvector centrality of TAS2R46 nodes. The TMs and loops are highlighted as well as residues pinpointed in previous experimental analysis. Results showed higher centrality of TM6 with strychnine, especially for H2055.68, H2246.31, and Y2416.48, and decreased centralities in the Trans state. (C) Visual representation of the dynamic networks, where the receptor is viewed from the IC region. The edges of the network are red cylinders with a radius proportional to the betweenness centrality of the edge.CC BY · PubMed Central
FIGURE 6 Visual representation of the optimal path connecting strychnine and G protein-binding residues. The left column represents the communication path between W883.32 in TM3, highlighted as a green sphere, and H2246.31 in TM6, represented as a cyan sphere. The right column represents the communication path between E2657.39 in TM7, highlighted as a green sphere, and Y1063.50 in TM3, represented as a cyan sphere. The edges in the paths are represented by cylinders whose radius is proportional to the generalized correlation coefficient between residues.
FIGURE 6 Visual representation of the optimal path connecting strychnine and G protein-binding residues. The left column represents the communication path between W883.32 in TM3, highlighted as a green sphere, and H2246.31 in TM6, represented as a cyan sphere. The right column represents the communication path between E2657.39 in TM7, highlighted as a green sphere, and Y1063.50 in TM3, represented as a cyan sphere. The edges in the paths are represented by cylinders whose radius is proportional to the generalized correlation coefficient between residues.CC BY · PubMed Central

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Metadata

Authors
Cannariato, M., Fanunza, R., Zizzi, E. A., Miceli, M., Di Benedetto, G., Deriu, M. A., & Pallante, L.
Affiliations
Politecnico di Torino (IT)
Corresponding author
Pallante, Lorenzo
ORCID
Venue
Frontiers in Molecular Biosciences
Publisher
openRxiv
Published
2023-11-21
Volume
11
Pages
1473675-1473675
ISSN
2296-889X (ISSN-L)
DOI
10.1101/2023.11.21.568072
PMC
PMC11646861
OpenAlex
W4404899993
Cited by
10
References
1
Citations by year
2026: 5 · 2025: 3 · 2024: 1 · 2023: 1
FWCI
1.22
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Molecular Biosciences (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PORTO@Iris (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • European Commission (872181, HORIZON2020)
  • HORIZON EUROPE Framework Programme (872181, HORIZON-MSCA-2023-SE-01)
  • H2020 Marie Skłodowska-Curie Actions (2023-SE-01, HORIZON-MSCA-2023-SE-01, 872181)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Nursing › Nutrition and Dietetics › Biochemical Analysis and Sensing Techniques
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
bitter taste receptors, G protein-coupled receptors, strychnine, allosteric networks, conformational change, ligand binding, receptor dynamics, signal transduction, bitter taste perception

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