Membrane Model for the G-Protein-Coupled Receptor Rhodopsin: Hydrophobic Interface and Dynamical Structure

Thomas Huber, Ana V. Botelho, Klaus Beyer, Michael F Brown

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Rhodopsin is the only member of the pharmacologically important superfamily of G-protein-coupled receptors with a known structure at atomic resolution. A molecular dynamics model of rhodopsin in a POPC phospholipid bilayer was simulated for 15 ns, revealing a conformation significantly different from the recent crystal structures. The structure of the bilayer compared with a protein-free POPC control indicated hydrophobic matching with the nonpolar interface of the receptor, in agreement with deuterium NMR experiments. A new generalized molecular surface method, based on a three-dimensional Voronoi cell construction for atoms with different radii, was developed to quantify cross-sectional area profiles for the protein, lipid acyl chains and headgroups, and water. Thus, it was possible to investigate the bilayer deformation due to curvature of the individual lipid monolayers. Moreover, the generalized molecular surface derived hydrophobic interface allowed benchmarking of the hydropathy sequence analysis, an important structural genomics tool. Five water molecules diffused into internal hydration sites during the simulation, yielding a total of 12 internal waters. The cytoplasmic loops and the C-terminal tail, containing the G-protein recognition and protein sorting sequences, exhibited a high mobility, in marked contrast to the extracellular and transmembrane domains. The proposed functional coupling of the highly conserved ERY motif to the lipid-water interface via the cytoplasmic loops provides insight into lipid effects on G-protein-coupled receptor activation in terms of a flexible surface model, involving the spontaneous monolayer curvature.

Original languageEnglish (US)
Pages (from-to)2078-2100
Number of pages23
JournalBiophysical Journal
Volume86
Issue number4
StatePublished - Apr 2004

Fingerprint

Rhodopsin
G-Protein-Coupled Receptors
Lipids
Membranes
Water
Benchmarking
Molecular Models
Deuterium
Protein Transport
Molecular Dynamics Simulation
Genomics
GTP-Binding Proteins
Sequence Analysis
Phospholipids
Proteins

ASJC Scopus subject areas

  • Biophysics

Cite this

Membrane Model for the G-Protein-Coupled Receptor Rhodopsin : Hydrophobic Interface and Dynamical Structure. / Huber, Thomas; Botelho, Ana V.; Beyer, Klaus; Brown, Michael F.

In: Biophysical Journal, Vol. 86, No. 4, 04.2004, p. 2078-2100.

Research output: Contribution to journalArticle

@article{7cdef38a55364b66ac0fc9e25de4fd35,
title = "Membrane Model for the G-Protein-Coupled Receptor Rhodopsin: Hydrophobic Interface and Dynamical Structure",
abstract = "Rhodopsin is the only member of the pharmacologically important superfamily of G-protein-coupled receptors with a known structure at atomic resolution. A molecular dynamics model of rhodopsin in a POPC phospholipid bilayer was simulated for 15 ns, revealing a conformation significantly different from the recent crystal structures. The structure of the bilayer compared with a protein-free POPC control indicated hydrophobic matching with the nonpolar interface of the receptor, in agreement with deuterium NMR experiments. A new generalized molecular surface method, based on a three-dimensional Voronoi cell construction for atoms with different radii, was developed to quantify cross-sectional area profiles for the protein, lipid acyl chains and headgroups, and water. Thus, it was possible to investigate the bilayer deformation due to curvature of the individual lipid monolayers. Moreover, the generalized molecular surface derived hydrophobic interface allowed benchmarking of the hydropathy sequence analysis, an important structural genomics tool. Five water molecules diffused into internal hydration sites during the simulation, yielding a total of 12 internal waters. The cytoplasmic loops and the C-terminal tail, containing the G-protein recognition and protein sorting sequences, exhibited a high mobility, in marked contrast to the extracellular and transmembrane domains. The proposed functional coupling of the highly conserved ERY motif to the lipid-water interface via the cytoplasmic loops provides insight into lipid effects on G-protein-coupled receptor activation in terms of a flexible surface model, involving the spontaneous monolayer curvature.",
author = "Thomas Huber and Botelho, {Ana V.} and Klaus Beyer and Brown, {Michael F}",
year = "2004",
month = "4",
language = "English (US)",
volume = "86",
pages = "2078--2100",
journal = "Biophysical Journal",
issn = "0006-3495",
publisher = "Biophysical Society",
number = "4",

}

TY - JOUR

T1 - Membrane Model for the G-Protein-Coupled Receptor Rhodopsin

T2 - Hydrophobic Interface and Dynamical Structure

AU - Huber, Thomas

AU - Botelho, Ana V.

AU - Beyer, Klaus

AU - Brown, Michael F

PY - 2004/4

Y1 - 2004/4

N2 - Rhodopsin is the only member of the pharmacologically important superfamily of G-protein-coupled receptors with a known structure at atomic resolution. A molecular dynamics model of rhodopsin in a POPC phospholipid bilayer was simulated for 15 ns, revealing a conformation significantly different from the recent crystal structures. The structure of the bilayer compared with a protein-free POPC control indicated hydrophobic matching with the nonpolar interface of the receptor, in agreement with deuterium NMR experiments. A new generalized molecular surface method, based on a three-dimensional Voronoi cell construction for atoms with different radii, was developed to quantify cross-sectional area profiles for the protein, lipid acyl chains and headgroups, and water. Thus, it was possible to investigate the bilayer deformation due to curvature of the individual lipid monolayers. Moreover, the generalized molecular surface derived hydrophobic interface allowed benchmarking of the hydropathy sequence analysis, an important structural genomics tool. Five water molecules diffused into internal hydration sites during the simulation, yielding a total of 12 internal waters. The cytoplasmic loops and the C-terminal tail, containing the G-protein recognition and protein sorting sequences, exhibited a high mobility, in marked contrast to the extracellular and transmembrane domains. The proposed functional coupling of the highly conserved ERY motif to the lipid-water interface via the cytoplasmic loops provides insight into lipid effects on G-protein-coupled receptor activation in terms of a flexible surface model, involving the spontaneous monolayer curvature.

AB - Rhodopsin is the only member of the pharmacologically important superfamily of G-protein-coupled receptors with a known structure at atomic resolution. A molecular dynamics model of rhodopsin in a POPC phospholipid bilayer was simulated for 15 ns, revealing a conformation significantly different from the recent crystal structures. The structure of the bilayer compared with a protein-free POPC control indicated hydrophobic matching with the nonpolar interface of the receptor, in agreement with deuterium NMR experiments. A new generalized molecular surface method, based on a three-dimensional Voronoi cell construction for atoms with different radii, was developed to quantify cross-sectional area profiles for the protein, lipid acyl chains and headgroups, and water. Thus, it was possible to investigate the bilayer deformation due to curvature of the individual lipid monolayers. Moreover, the generalized molecular surface derived hydrophobic interface allowed benchmarking of the hydropathy sequence analysis, an important structural genomics tool. Five water molecules diffused into internal hydration sites during the simulation, yielding a total of 12 internal waters. The cytoplasmic loops and the C-terminal tail, containing the G-protein recognition and protein sorting sequences, exhibited a high mobility, in marked contrast to the extracellular and transmembrane domains. The proposed functional coupling of the highly conserved ERY motif to the lipid-water interface via the cytoplasmic loops provides insight into lipid effects on G-protein-coupled receptor activation in terms of a flexible surface model, involving the spontaneous monolayer curvature.

UR - http://www.scopus.com/inward/record.url?scp=1942519744&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1942519744&partnerID=8YFLogxK

M3 - Article

C2 - 15041649

AN - SCOPUS:1942519744

VL - 86

SP - 2078

EP - 2100

JO - Biophysical Journal

JF - Biophysical Journal

SN - 0006-3495

IS - 4

ER -