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Review
. 2020 Feb 28;48(1):25-37.
doi: 10.1042/BST20190149.

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

Robin A Corey  1 , Phillip J Stansfeld  1   2 , Mark S P Sansom  1
Affiliations
Review

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

Robin A Corey et al. Biochem Soc Trans. .

Abstract

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.

Keywords: free energy; lipid; membrane protein; molecular dynamics; simulation.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. Identification of protein–lipid interactions.
(A) Left: view of bovine AAC (PDB 1OKC), with the protein shown as a grey cartoon and densities for CDL shown in yellow surface. Middle: A bound CDL molecule from the crystal structure is shown in yellow, orange, and red spheres. Right: close-up of one of the CDL molecules: the CDL and contacting residues are shown as sticks, with aromatic, hydrophobic, and small amino acid sidechains coloured green, acidic sidechains red, basic sidechains blue, and polar uncharged sidechains in purple. (B) As (A), but for human β2AR (PDB 3D4S), showing the binding mode of two cholesterol molecules. (C) As (A) but for G. gallus Kir2.2 (PDB 3SPI) in complex with di-C8-PIP2 molecules.
Figure 2.
Figure 2.. Equilibrium and free energy calculations for protein–lipid interactions.
(A) Equilibrium simulations allow multiple protein–lipid events to occur in an unbiased fashion over long MD simulations. (B) Construction of a reaction co-ordinate in physical space requires sampling of the protein–lipid complex (State 1) and of the lipid free in membrane (State 0) as well as many intermediate positions of the lipid between the binding site and surrounding bilayer bulk. Note that in State 0, the lipid binding site on the protein will be occupied by a generic lipid. (C) Sampling States 1 and 0 in chemical space. This is done over two sets of simulations: first, whilst bound to the protein, the target lipid (yellow) is alchemically transformed into a background (generic e.g. PC; grey) lipid (upper panels). At the same time, a background lipid free in the bilayer is also transformed in a target lipid molecule. Combining the upper and lower calculations yields the free energy for binding of the target lipid relative to that of a background lipid.
Figure 3.
Figure 3.. Computational estimates of protein–lipid interaction free energies.
(A) Summary of estimates of free energies for integral protein interactions of cholesterol (green), CDL (purple), and PIP2 (orange). The data for this graph were derived from the range of simulation studies (both coarse-grained and atomistic) discussed in the main text. Data are plotted as box and whiskers, showing the 5–95 percentile range. Data plotted in Prism 7 (GraphPad). (B) Cholesterol, CDL, and PIP2, indicating the likely charge state of the anionic lipids.
Figure 4.
Figure 4.. Energetics of interaction of the GRP1 PH domain with a PIP3-containing lipid bilayer.
(A) Simulations of the interaction of the GRP1 PH domain (grey) with a lipid bilayer. The double-headed arrow indicates the reaction co-ordinate for estimation of the free energy landscape (PMF) as a function of the distance of the PH domain from the target lipid molecule(s). (B) The GRP1 PH domain is shown bound to a PIP3-containing bilayer. PIP3 molecules are shown as yellow spheres. Lipids are shown as green sticks. Simulation co-ordinates from [95].
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References

    1. Gupta K., Donlan J.A.C., Hopper J.T.S., Uzdavinys P., Landreh M., Struwe W.B. et al. (2017) The role of interfacial lipids in stabilizing membrane protein oligomers. Nature 541, 421–424 10.1038/nature20820 - DOI - PMC - PubMed
    1. Parker J.L., Corey R.A., Stansfeld P.J. and Newstead S. (2019) Structural basis for substrate specificity and regulation of nucleotide sugar transporters in the lipid bilayer. Nat. Commun. 10, 4657 10.1038/s41467-019-12673-w - DOI - PMC - PubMed
    1. Wen P.C., Mahinthichaichan P., Trebesch N., Jiang T., Zhao Z.Y., Shinn E. et al. (2018) Microscopic view of lipids and their diverse biological functions. Curr. Opin. Struct. Biol. 51, 177–186 10.1016/j.sbi.2018.07.003 - DOI - PMC - PubMed
    1. Corradi V., Sejdiu B.I., Mesa-Galloso H., Abdizadeh H., Noskov S.Y., Marrink S.J. et al. (2019) Emerging diversity in lipid–protein interactions. Chem. Rev. 119, 5775–5848 10.1021/acs.chemrev.8b00451 - DOI - PMC - PubMed
    1. Manna M., Nieminen T. and Vattulainen I. (2019) Understanding the role of lipids in signaling through atomistic and multiscale simulations of cell membranes. Ann. Rev. Biophys. 48, 421–439 10.1146/annurev-biophys-052118-115553 - DOI - PubMed

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