Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
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Chapter 10. Synthetic Receptors for Polar Lipids
Kasey J. Clear and Bradley D. Smith*
Department of Chemistry and Biochemistry,
236 Nieuwland Science Hall, University of Notre Dame,
Notre Dame, 46556 IN, USA
*Email: smith.115@nd.edu
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
© The Royal Society of Chemistry 2015
Table 10.1 Major classes of lipids found in biological systems. R indicates a fatty acid tail of varying length and saturation.
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
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Table 10.2 Polar lipid self-assembly is controlled by the lipid packing parameter, P. (Table adapted from Rev. Biophys.,
1980, 13, 121)
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
© The Royal Society of Chemistry 2015
Table 10.3 Approximate polar lipid composition (by mass) in various biological membranes.
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B. Alberts, Molecular Biology of the Cell, Garland Science, 2008.
J. Löffler, H. Einsele, H. Hebart, U. Schumacher, C. Hrastnik and G. Daum, FEMS Microbiol. Lett., 2000, 185, 59.
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Scheme 10.1 Hydrophobic tail recognition of polar lipids.
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
© The Royal Society of Chemistry 2015
Figure 10.1 Bovine NPC2 cholesterol transport protein binds the hydrophobic tail of cholesterol. The crystal
structure of the NPC2-cholesterol sulfate complex (PDB code code 2HKA) (left) and cartoon representation of
the NPC2-cholesterol complex (right). (Reprinted with permission from J. Biol. Chem., 2007, 282, 23525, ©
2007 American Society for Biochemistry and Molecular Biology)
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
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Scheme 10.2 Names and headgroup structures of phospholipids.
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
© The Royal Society of Chemistry 2015
Table 10.4 Currently known lipid binding domains found in peripheral membrane proteins. (Table adapted by permission
from Nat. Rev. Mol. Cell Biol., 2008, 9, 99, © Macmillan Publishers Ltd 2008)
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Scheme 10.3 (left) Headgroup recognition of a polar lipid at a membrane surface using noncovalent interactions (e.g., hydrogen bonding, electrostatics, metal cation coordination). (right)
Biological strategies for improving polar lipid recognition at a membrane surface: (A) Partial
hydrophobic insertion into membrane; (B) Oligomerization of protein monomer upon lipid binding;
(C) Coincidence detection of two lipid types in a membrane; (D) Coincidence detection of a lipid and
transmembrane protein.
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Figure 10.2 (left) Crystal structure of the EEA1 FYVE domain bound to D-myo-inositol-1,3bisphosphate, the headgroup of PI(3)P (PDB code 1JOC). (Molecular graphics image was produced
using the Chimera package from the Computer Graphics Laboratory, University of California, San
Francisco; supported by NIH P41 RR-01081) (right) Structural illustration of the binding interactions
showing hydrogen bonding and salt bridges between protein side chains and PI(3)P.
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
© The Royal Society of Chemistry 2015
Figure 10.3 Phosphatidylserine (PS) headgroup recognition by annexin V, highlighting the requirement of
two Ca2+ ions, which, interact with the PS phosphate and carboxylate groups. (PDB code 1A8A).
(Molecular graphics image was produced using the Chimera package from the Computer Graphics
Laboratory, University of California, San Francisco; supported by NIH P41 RR-01081)
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
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Figure 10.4 (upper) Peptide sequences of PE-binding lantibiotics cinnamycin and duramycin. (lower left)
Cinnamycin complexed with lyso-PE from NMR-resolved solution structure showing small binding cleft for
ammonium of PE and adjacent carboxylate (PDB code 2DDE). (lower right) Structural illustration of binding
event. (Molecular graphics image was produced using the Chimera package from the Computer Graphics
Laboratory, University of California, San Francisco; supported by NIH P41 RR-01081)
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Scheme 10.4 (A) Ditopic mode of recognition of polar lipids by simultaneous binding of headgroup
and tail in membrane. Aggregation of lipid-ditopic receptor complexes can lead to (B) barrel stavetype membrane pores or (C) aggregate located within or outside the membrane.
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Scheme 10.5 Chemical structures of polyene macrocyclic natural products, filipin and amphotericin
B (AmB) which act as ditopic receptors for cholesterol and ergosterol, respectively.
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
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Table 10.5 Common container molecules used for encapsulation of lipids and their typical guests.
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Scheme 10.6 (A) Dimensions of cholesterol and (B) cone-shaped cyclodextrin rings composed of 6, 7 or 8 D-glucose
monomers (α, β, or γ-CD). (Figure adapted with permission from Steroids, 2011, 76, 216, © Elsevier 2011)
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
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Table 10.6 β-Cyclodextrin bimolecular association constants for monomeric and dimeric systems.
Scheme 10.7 (left) Schematic of βCD dimers and the corresponding linker structures listed in Table 10.6. (right) Structure of
N-retinylidine-N-ethanolamine (A2E), a bisretinoid that accumulates in macular degenerative disease.
Table 10.7 Binding constants and fluorescent response for the molecular tube hosts and fatty acid guests shown in Figure 10.5.
Figure 10.5 The chemical structures and structural models of molecular tubes 10.1 and 10.2, highlighting the collapsed
conformation of 10.1 and open conformation of 10.2 (R = CH2CO2H in both structures). Shown on the right are the structures of
two fatty acid guests. (Adapted with permission from J. Org. Chem., 2012, 77, 851, © 2012 American Chemical Society)
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
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Scheme 10.8 (A) General structures of tris(2-aminoethylamine) (TREN) amide and sulfonamide hydrogen bonding
receptors for phospholipid headgroups, shown here interacting with the phosphate of PC. (B) Structures of cholate
bis-urea receptors and proposed model of phosphate headgroup recognition.
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Scheme 10.9 Synthetic receptors for bacterial Lipid A. (A) Cationic cholate derivatives and (B)
Cycloalkane compounds with appended L-Trp (C-terminal linkage).
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Figure 10.6 Peptide mimics of PS-binding lactadherin protein. (left) Computational modeling of PS headgroup in
protein binding site. (right) Structure of cyclic peptides designed as small molecule lactadherin mimics. (Reprinted with
permission from J. Am. Chem. Soc., 2011, 133, 15280, © 2011 American Chemical Society)
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
© The Royal Society of Chemistry 2015
Scheme 10.10 Phosphate ester recognition using zinc(II)-bisdipicolylamine (Zn2BDPA) coordination complexes.
(A) Generic scheme for phosphate monoester binding. (B) Possible binding modes for PS headgroup recognition by
Zn2BDPA at the membrane surface.
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Figure 10.7 (left) Cell death imaging probe 10.12 composed of Zn2BDPA linked to a near-infrared
fluorescent dye. (right) False colored fluorescence image of a living rat bearing two tumors. There is
increased accumulation of the cell death probe in the tumor that has been treated by focal beam
radiation.
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Scheme 10.11 Strategies for improved probe affinity for PS-rich membranes. (A) Modified Zn2BDPA
structure exhibits enhanced recognition of the PS headgroup by incorporation of secondary
hydrogen bonding and hydrophobic interactions. (B) Multivalent structure with four Zn2BDPA groups.
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Figure 10.8 (A) Receptor 10.13 shown interacting with two PI(4,5)P2 headgroups through hydrogen bonding
between the urea and phosphate and the site for boronic ester formation between the boronic acid and PI(4,5)P2
cis-diol. (B) Modeling of 10.13 (dark) bound to two triphosphate headgroups (light). (Reproduced with permission
from ACS Chem. Biol., 2011, 6, 1382, © 2011 American Chemical Society)
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
© The Royal Society of Chemistry 2015
Scheme 10.12