Vibrational Energy Transfer Rates and Energy Exchange Networks in G-Protein coupled Receptors

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Authors

Poudel, Humanath

Issue Date

2023

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Dissertation

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The central focus of this study is the computational modeling of vibrational energy transport in G-protein coupled receptors (GPCRs) to investigate important questions such as ligand-mediated structural and dynamic changes that contribute to allosteric regulations of GPCRs. We also aim to investigate the signaling pathways and activation-induced reorganization of energy transport networks. The other questions include exploring the role of transmembrane water for GPCR activation and deriving the connection between the rates of vibrational energy transfer and contact dynamics at room temperature. First, we start with investigating the relationship between the rates of vibrational energy transfer and equilibrium structural fluctuations across van der Waals (vdW) and polar contacts of a globular protein, villin headpiece subdomain HP36, at room temperature, 300 K. HP36 is a smaller protein, consisting of 36 amino acids, thus a good system to start with, and some of these properties have been studied in the past at low temperature. We found the rates of vibrational energy transfer across vdW and polar contacts are proportional to the inverse variance of the contact length.We carried out molecular dynamics simulations of class A GPCR, β2 adrenergic receptor (β2AR), a neurotransmitter receptor, in inactive and active states and modeled the vibrational energy transport throughout the protein to examine the vibrational signaling pathways and activation-induced reorganizations of non-covalent networks. We constructed the Energy Exchange Networks (EENs) of β2AR in both states. To identify the changes in communication in GPCR activation, the difference in energy exchange networks, ΔEEN, and the relative difference in energy exchange networks, rΔEEN, were computed. We observe the rΔEEN of β2AR is efficient to capture all crucial changes including the change in vdW contacts and conserved motif residues that rearrange upon activation contributing to the allosteric transition of the GPCR. We report a branched pathway that passes across the β2AR from the ligand to the cytoplasm. We extend our analysis of non-covalent ii networks of β2AR, intending to utilize cost-effective approaches, using the inter-residue distance-based Protein Contact Networks, PCNs. We compared the results of PCNs with EENs and the similarities and differences between the two methods are discussed. We further extended the investigation on β2AR to examine the relationship between the rates of vibrational energy transfer and contact dynamics across vdW and polar contacts to estimate the entropic changes associated with the change in the dynamics of the contacts with change in protein states. We report that the active state has a lower packing density and larger flexibility compared to the inactive state. The entropic contribution in activation of the GPCR associated with the change in contact dynamics with the change in the protein states is reported and the contributions of contact dynamics to allostery is discussed. Lastly, we simulated a class B GPCR, Glucagon like peptide-1 receptor in inactive, small molecule-bound active, and peptide-bound active states to examine the signaling pathways and the role of transmembrane water in activation. We report the reorganized networks upon activation in terms of energy transport networks. We show that the relaxation of water in the active states is slow compared to the inactive state due to the formation of stable protein-water hydrogen bonds in the active states thereby contributing to the stabilization of the GPCR in activation.

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