State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes

Song, Wanling; Yen, Hsin‐Yung; Robinson, Carol V.; Sansom, Mark S.P.

doi:10.1016/j.str.2018.10.024

Cited by 88 publications

(167 citation statements)

References 88 publications

(96 reference statements)

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“…PIP 2 interactions have also been investigated with many receptors including GPCRs [31]. For example, free energies for binding to the A 2A R receptor range from −10 to −80 kJ mol −1 depending on the conformational state of the receptor [44]. This state dependence of binding to the receptor suggests PIP 2 may be an allosteric regulator of A 2A R, as has been suggested experimentally to be the case for other anionic lipids and GPCRs [74].…”

Section: Binding Of Anionic Lipids To Membrane Proteinsmentioning

confidence: 90%

“…There are many more 'targeted' approaches to estimating free energies of protein-lipid interactions, of which potential of mean force (PMF) calculations are the most widely used (e.g. [24,29,44]). These can provide a cross-section through a more complex free energy landscape, showing the free energy of a lipid/protein system as a function of a typically one-dimensional reaction co-ordinate, e.g.…”

Section: Potential Of Mean Force Calculationsmentioning

confidence: 99%

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The energetics of protein–lipid interactions as viewed by molecular simulations

Corey

Stansfeld

Sansom

2019

Biochemical Society Transactions

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Membranes are formed from a bilayer containing diverse lipid species with which membrane proteins interact. Integral, membrane proteins are embedded in this bilayer, where they interact with lipids from their surroundings, whilst peripheral membrane proteins bind to lipids at the surface of membranes. Lipid interactions can influence the function of membrane proteins, either directly or allosterically. Both experimental (structural) and computational approaches can reveal lipid binding sites on membrane proteins. It is, therefore, important to understand the free energies of these interactions. This affords a more complete view of the engagement of a particular protein with the biological membrane surrounding it. Here, we describe many computational approaches currently in use for this purpose, including recent advances using both free energy and unbiased simulation methods. In particular, we focus on interactions of integral membrane proteins with cholesterol, and with anionic lipids such as phosphatidylinositol 4,5-bis-phosphate and cardiolipin. Peripheral membrane proteins are exemplified via interactions of PH domains with phosphoinositide-containing membranes. We summarise the current state of the field and provide an outlook on likely future directions of investigation.

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Section: Binding Of Anionic Lipids To Membrane Proteinsmentioning

confidence: 90%

Section: Potential Of Mean Force Calculationsmentioning

confidence: 99%

The energetics of protein–lipid interactions as viewed by molecular simulations

Corey

Stansfeld

Sansom

2019

Biochemical Society Transactions

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“…Despite current knowledge, to date, only one selective A2aR agonist (Regadenoson) has gained FDA approval, as well as an antagonist (Istradefylline), which in combination with levodopa is used for the treatment of Parkinson's disease in Japan [58,59]. A2aR is an ideal system to study GPCR activation processes because it has a high propensity for binding lipid allosteric modulators [60], is a well-known drug target for several agonists and antagonists, and has been the focus of recent NMR studies [42,[61][62][63][64]. These studies show that, upon the addition of a full agonist, A2aR activation follows outward movements of TM5 and TM6 (including rotation in the latter), an inward shift of the intracellular part of TM7, and a vertical translation of TM3 [42,[61][62][63][64].…”

Section: Introductionmentioning

confidence: 99%

Insights into adenosine A2A receptor activation through cooperative modulation of agonist and allosteric lipid interactions

2020

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The activation process of G protein-coupled receptors (GPCRs) has been extensively studied, both experimentally and computationally. In particular, Molecular Dynamics (MD) simulations have proven useful in exploring GPCR conformational space. The typical behaviour of class A GPCRs, when subjected to unbiased MD simulations from their crystallized inactive state, is to fluctuate between inactive and intermediate(s) conformations, even with bound agonist. Fully active conformation(s) are rarely stabilized unless a G protein is also bound. Despite several crystal structures of the adenosine A2a receptor (A2aR) having been resolved in complex with co-crystallized agonists and G s protein, its agonist-mediated activation process is still not completely understood. In order to thoroughly examine the conformational landscape of A2aR activation, we performed unbiased microsecond-length MD simulations in quadruplicate, starting from the inactive conformation either in apo or with bound agonists: endogenous adenosine or synthetic NECA, embedded in two homogeneous phospholipid membranes: 1,2-dioleoyl-sn-glycerol-3-phosphoglycerol (DOPG) or 1,2-dioleoyl-sn-glycerol-3-phosphocholine (DOPC). In DOPC with bound adenosine or NECA, we observe transition to an intermediate receptor conformation consistent with the known adenosine-bound crystal state. In apo state in DOPG, two different intermediate conformations are obtained. One is similar to that observed with bound adenosine in DOPC, while the other is closer to the active state but not yet fully active. Exclusively, in DOPG with bound adenosine or NECA, we reproducibly identify receptor conformations with fully active features, which are able to dock G s protein. These different receptor conformations can be attributed to the action/absence of agonist and phospholipid-mediated allosteric effects on the intracellular side of the receptor.

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“…Selent and collaborators have reported following both experimental and computational studies that Chol can enter the adenosine A 2A receptor (A 2A R) binding pocket from the membrane milieu through a gate used for opsin ligands . Yet, another recent study on this same receptor revealed a certain correlation between the strength of lipid contacts, including Chol, and the degree of dependence on the receptor‐conformational states, suggesting lipids to regulate receptor‐conformational dynamics . Studies on Chol impact on CCR5 activation and pharmacology by a direct method using theoretical MD or other biophysical approaches in lipid membranes whose lipid composition is tightly controlled are still missing.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol impacts chemokine CCR5 receptor ligand‐binding activity

Calmet

Cullin

Cortès³

et al. 2019

The FEBS Journal

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The chemokine CCR5 receptor is target of maraviroc, a negative allosteric modulator of CCR5 that blocks the HIV protein gp120 from associating with the receptor, thereby inhibiting virus cellular entry. As noted with other G‐protein‐coupled receptor family members, the role of the lipid environment in CCR5 signaling remains obscure and very modestly investigated. Controversial literature on the impact of cholesterol (Chol) depletion in HIV infection and CCR5 signaling, including the hypothesis that Chol depletion could inhibit HIV infection, lead us to focus on the understanding of Chol impact in the first stages of receptor activation. To address this aim, the approach chosen was to employ reconstituted model lipid systems of controlled lipid composition containing CCR5 from two distinct expression systems: Pichia pastoris and cell‐free expression. The characterization of receptor/ligand interaction in terms of total binding or competition binding assays was independently performed by plasmon waveguide resonance and fluorescence anisotropy, respectively. Maraviroc, a potent receptor antagonist, was the ligand investigated. Additionally, coarse‐grained molecular dynamics simulation was employed to investigate Chol impact in the receptor‐conformational flexibility and dynamics. Results obtained with receptor produced by different expression systems and using different biophysical approaches clearly demonstrate a considerable impact of Chol in the binding affinity of maraviroc to the receptor and receptor‐conformational dynamics. Chol considerably decreases maraviroc binding affinity to the CCR5 receptor. The mechanisms by which this effect occurs seem to involve the adoption of distinct receptor‐conformational states with restrained structural dynamics and helical motions in the presence of Chol.

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State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes

Cited by 88 publications

References 88 publications

The energetics of protein–lipid interactions as viewed by molecular simulations

The energetics of protein–lipid interactions as viewed by molecular simulations

Insights into adenosine A2A receptor activation through cooperative modulation of agonist and allosteric lipid interactions

Cholesterol impacts chemokine CCR5 receptor ligand‐binding activity

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