Role of Cholesterol and Polyunsaturated Chains in Lipid−Protein Interactions:  Molecular Dynamics Simulation of Rhodopsin in a Realistic Membrane Environment

Pitman, Michael C.; Grossfield, Alan; Suits, Frank; Feller, Scott E.

doi:10.1021/ja042715y

Cited by 133 publications

(130 citation statements)

References 23 publications

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“…This follows our protocol previously applied to rhodopsin (30,36,(45)(46)(47). In developing the protocol, we have specifically investigated the consequences of long time constant volume simulations for membrane-GPCR systems, after the volume has been equilibrated to 1 atm of pressure.…”

Section: Methodsmentioning

confidence: 99%

A Lipid Pathway for Ligand Binding Is Necessary for a Cannabinoid G Protein-coupled Receptor

Hurst

Grossfield

Lynch

et al. 2010

Journal of Biological Chemistry

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197

242

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The cannabinoid receptors belong to the class A (rhodopsin family) of G protein-coupled receptors (GPCRs).2 The second cannabinoid receptor subtype, CB2 (2), is highly expressed throughout the immune system (3, 4) and has been described in the central nervous system under both pathological (5) and physiological conditions (6). All known CB2 ligands are highly lipophilic. In fact, the CB2 endogenous cannabinoid, sn-2-arachidonoylglycerol (2-AG) (7,8), is synthesized on demand from the lipid bilayer itself in a two-step process in which phospholipase C-␤ hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate diacylglycerol, which is then hydrolyzed by diacylglycerol lipase to yield 2-AG (9, 10). After 2-AG interaction with the membraneembedded CB receptor, it is hydrolyzed to arachidonic acid and glycerol by a membrane-associated enzyme, monoacylglycerol lipase (11). As revealed by the crystal structures of rhodopsin (12-15), the ␤ 2 -adrenergic receptor (AR) (16 -18), ␤ 1 -AR (19), and adenosine A2A receptor (20), the general topology of a GPCR includes the following: 1) an extracellular (EC) N terminus; 2) seven transmembrane ␣-helices (TMHs) arranged to form a closed bundle; 3) loops connecting TMHs that extend intra-and extracellularly; and 4) an intracellular (IC) C terminus that begins with a short helical segment (helix 8) oriented parallel to the membrane surface. Agonists bind inside the crevice formed by the TMH bundle and produce conformational changes on the IC face of the receptor that uncover previously masked G protein-binding sites (21), which then lead to G protein coupling. Biophysical studies using a variety of techniques indicate that ligand-induced receptor activation produces the following changes: 1) a conformational change in the W6.48 "toggle switch" within the ligand binding pocket (22); 2) a change in the relative orientations of TMH3 and -6 that breaks an IC "ionic lock" (23-28), with the intracellular end of TMH6 moving away from TMH3 by hinging and moving up toward lipid (27); 3) the uptake of two protons (29); and 4) an influx of water (30).Recent isothiocyanate covalent labeling studies have suggested that a classical cannabinoid, AM841, enters the CB2 receptor via the lipid bilayer (1). However, the sequence of steps involved in such a lipid pathway entry has not yet been elucidated. We report here microsecond time scale unbiased

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Section: Methodsmentioning

confidence: 99%

A Lipid Pathway for Ligand Binding Is Necessary for a Cannabinoid G Protein-coupled Receptor

Hurst

Grossfield

Lynch

et al. 2010

Journal of Biological Chemistry

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197

242

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“…[44][45][46][47][48][49] Each of these studies has something of value to add to our understanding of the molecular nature of rhodopsin and its activation by light. Each group has made different choices with respect to membrane representation, length of simulation, size of simulation, and treatment of electrostatics.…”

Section: Initial Events In Photoactivationmentioning

confidence: 99%

How a small change in retinal leads to G‐protein activation: Initial events suggested by molecular dynamics calculations

Stevens

Woolf

2006

Proteins

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Rhodopsin is the prototypical G-protein coupled receptor, coupling light activation with high efficiency to signaling molecules. The dark-state X-ray structures of the protein provide a starting point for consideration of the relaxation from initial light activation to conformational changes that may lead to signaling. In this study we create an energetically unstable retinal in the light activated state and then use molecular dynamics simulations to examine the types of compensation, relaxation, and conformational changes that occur following the cis-trans light activation. The results suggest that changes occur throughout the protein, with changes in the orientation of Helices 5 and 6, a closer interaction between Ala 169 on Helix 4 and retinal, and a shift in the Schiff base counterion that also reflects changes in sidechain interactions with the retinal. Taken together, the simulation is suggestive of the types of changes that lead from local conformational change to light-activated signaling in this prototypical system.

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“…Two of these systems, a small solvated lipid bilayer system, SOPE, and a solvated membrane protein system, Rhodopsin, have been used in published scientific work by the Blue Matter science team [5,23,24]. The third, the 92,224 atom ApoA1 solvated lipoprotein system, is used as a benchmark by the NAMD package [13].…”

Section: Performance Resultsmentioning

confidence: 99%

“…This supports one of the aims of the scientific component of the project, to carry out simulations on a scale that allows meaningful comparisons with experimental data. Results on a 43,222 atom protein/lipid system obtained from early production use of prototype Blue Gene/L hardware were recently published in the Journal of the American Chemical Society [5], another paper on the same system in in press and larger scale studies including microsecondscale simulations of solvated protein and membrane protein systems are currently underway.…”

Section: Introductionmentioning

confidence: 99%

“…The two main requirements are that the force field parameters be properly implemented, and that the integrator correctly measures the forces on each atom and makes the appropriate update of position and velocity for each time step. The JACS publication [5] was based on a 118ns NVE simulation of a membrane-bound protein, and the total and kinetic energy drift over that long period of simulation was negligible, indicating that there was consistently correct bookkeeping and integration of all the interaction forces.…”

Section: Introductionmentioning

confidence: 99%

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Blue Matter: Strong Scaling of Molecular Dynamics on Blue Gene/L

Fitch

Rayshubskiy

Eleftheriou

et al. 2006

Lecture Notes in Computer Science

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Abstract. This paper presents strong scaling performance data for the Blue Matter molecular dynamics framework using a novel n-body spatial decomposition and a collective communications technique implemented on both MPI and low level hardware interfaces. Using Blue Matter on Blue Gene/L, we have measured scalability through 16,384 nodes with measured time per time-step of under 2.3 milliseconds for a 43,222 atom protein/lipid system. This is equivalent to a simulation rate of over 76 nanoseconds per day and represents an unprecedented time-to-solution for biomolecular simulation as well as continued speed-up to fewer than three atoms per node. On a smaller, solvated lipid system with 13,758 atoms, we have achieved continued speedups through fewer than one atom per node and less than 2 milliseconds/time-step. On a 92,224 atom system, we have achieved floating point performance of over 1.8 TeraFlops/second on 16,384 nodes. Strong scaling of fixed-size classical molecular dynamics of biological systems to large numbers of nodes is necessary to extend the simulation time to the scale required to make contact with experimental data and derive biologically relevant insights.

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Role of Cholesterol and Polyunsaturated Chains in Lipid−Protein Interactions: Molecular Dynamics Simulation of Rhodopsin in a Realistic Membrane Environment

Cited by 133 publications

References 23 publications

A Lipid Pathway for Ligand Binding Is Necessary for a Cannabinoid G Protein-coupled Receptor

A Lipid Pathway for Ligand Binding Is Necessary for a Cannabinoid G Protein-coupled Receptor

How a small change in retinal leads to G‐protein activation: Initial events suggested by molecular dynamics calculations

Blue Matter: Strong Scaling of Molecular Dynamics on Blue Gene/L

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