Probing the energy landscape of the lipid interactions of the serotonin 1A receptor.

Autor: Mohole M; CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India., Naglekar A; CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India., Sengupta D; CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India. Electronic address: d.sengupta@ncl.res.in., Chattopadhyay A; CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India. Electronic address: amit@ccmb.res.in.
Jazyk: angličtina
Zdroj: Biophysical chemistry [Biophys Chem] 2024 Oct; Vol. 313, pp. 107289. Date of Electronic Publication: 2024 Jul 03.
DOI: 10.1016/j.bpc.2024.107289
Abstrakt: G protein-coupled receptors (GPCRs) are lipid-regulated transmembrane proteins that play a central role in cell signaling and pharmacology. Although the role of membrane lipids in GPCR function is well established, the underlying GPCR-lipid interactions have not been thermodynamically characterized due to the complexity of these interactions. In this work, we estimate the energetics and dynamics of lipid association from coarse-grain simulations of the serotonin 1A receptor embedded in a complex membrane. We show that lipids bind to the receptor with varying energetics of 1-4 kT, and timescales of 1-10 μs. The most favorable energetics and longest residence times are observed for cholesterol, glycosphingolipid GM1, phosphatidylethanolamine (PE) and phosphatidylserine (PS) lipids. Multi-exponential fitting of the contact probability suggests distinct dynamic regimes, corresponding to ps, ns and μs timescales, that we correlate with the annular, intermediate and non-annular lipid sites. The timescales of lipid binding correspond to high barrier heights, despite their relatively weaker energetics. Our results highlight that GPCR-lipid interactions are driven by both thermodynamic interactions and the dynamical features of lipid binding.
Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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