Dendritic Oligoglycerol Regioisomer Mixtures and Their Utility for Membrane Protein Research

Article abstract of DOI:10.1002/chem.202003991

Dendrons are an important class of macromolecules that can be used for a broad range of applications. Recent studies have indicated that mixtures of oligoglycerol detergent (OGD) regioisomers are superior to individual regioisomers for protein extraction. The origin of this phenomenon remains puzzling. Here we discuss the synthesis and characterization of dendritic oligoglycerol regioisomer mixtures and their implementation into detergents. We provide experimental benchmarks to support quality control after synthesis and investigate the unusual utility of OGD regioisomer mixtures for extracting large protein quantities from biological membranes. We anticipate that our findings will enable the development of mixed detergent platforms in the future.

Full text of DOI:10.1002/chem.202003991

Accepted Article
Accepted Article
Title: Dendritic oligoglycerol regioisomer mixtures and their utility for
membrane protein research
Authors: Leonhard Hagen Urner, Katharina Goltsche, Marleen Selent,
Idlir Liko, Marc-Philip Schweder, Carol V. Robinson, Kevin
Pagel, and Rainer Haag
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202003991
Link to VoR: https://doi.org/10.1002/chem.202003991
01/2020

10.1002/chem.202003991
Chemistry - A European Journal
FULL PAPER
Dendritic oligoglycerol regioisomer mixtures and their utility for
membrane protein research
Leonhard H. Urner,[a]* Katharina Goltsche,[a] Marleen Selent,[a] Idlir Liko,[b] Marc-Philip Schweder,[a]
Carol V. Robinson,[b] Kevin Pagel,[a] and Rainer Haag[a]
[a]
[b]
Dr. L. H. Urner, K. Goltsche, M. Selent, M.-P. Schweder,
Prof. Dr. K. Pagel, and Prof. Dr. R. Haag
Freie Universität Berlin
Institute of Chemistry and Biochemistry
Takustraße 3, 14195 Berlin
E-mail: leonhard.urner@fu-berlin.de
Dr. I. Liko, Prof. Dame C. Robinson
University of Oxford
Physical and Theoretical Chemistry Laboratory
South Parks Road
Oxford, OX13QZ
Supporting information for this article is given via a link at the end of the document.
Abstract: Dendrons are an important class of macromolecules that
can be used for a broad range of applications. Recent studies
indicated that mixtures of oligoglycerol detergent (OGD)
regioisomers are superior over individual regioisomers for protein
extraction. The origin of this phenomenon remains puzzling. Here we
discuss the synthesis and characterization of dendritic oligoglycerol
regioisomer mixtures and their implementation into detergents. We
provide experimental benchmarks to support quality control after
synthesis and investigate the unusual utility of OGD regioisomer
mixtures for extracting large protein quantities from biological
membranes. We anticipate that our findings will enable the
development of mixed detergent platforms in the future.
these advantageous properties makes dendritic oligoglycerol a
valuable starting material for structure-property studies.
Dendritic oligoglycerol has been used for the production of
dendronized polymers,[6] unimolecular micelles,[7] and dendritic
OGDs.[2] The first dendritic OGDs were reported by
Wyszogrodzka and co-workers in 2008.[8] Research has been
focused on understanding the relationship between molecular
structure and self-assembly as well as the utility of their
aggregates to be used for stabilizing water-in-fluorinated oil
emulsions[9] and solubilizing drugs or carbon nanotubes.[2]
Introduction
Almost 100 years ago, Hermann Staudinger pioneered the
theory of polymeric structures, which led to the emergence of a
research field, which we know as Macromolecular Chemistry.[1]
Until today, different classes of synthetic macromolecules have
been developed, such as linear polymers, hyperbranched
polymers, dendrons, and hybrid structures.[2] Unlike synthetic
polymers, which are polydisperse, the structure of a dendron is
perfectly defined. Dendrons contain
a single, chemically
addressable functional group at their center and multiple
functional groups at their periphery (Scheme 1). They are
classified by generations, which define their overall size and
number of peripheral groups. Their monodispersity and the
ability to gradually tune their molecular properties are valuable
perquisites for structure-property studies.[3]
The utility of glycerol for the production of dendrons and
related materials has been intensively investigated over the past
20 years.[2, 4] Glycerol is a green starting material. It is mainly
obtained as by-product from the vegetable oil industry, while
only small amounts are obtained from fossil chemicals.[5]
Dendritic oligoglycerol is non-ionic, water-soluble, biocompatible,
scalable in size, and straightforward to synthesize. The sum of
Scheme 1. First- [G1] and second-generation [G2] oligoglycerol dendrons
contain a single chemically addressable functional group at the core (focal
point). The number of hydroxyl groups at the periphery and their size varies
between the generations. Dendritic OGDs contain a hydrophilic head and a
hydrophobic tail. Regioisomers differ in terms of connectivity between glycerol
units in the head group. Mixtures of [G1] OGD regioisomers can extract more
protein quantities from membranes than individual regioisomers, but the origin
of this behaviour remains elusive.
1
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Recently, dendritic OGDs have been identified as versatile tools
for the structural analysis of important drug targets: membrane
proteins.[10] The modular architecture of dendritic OGDs can be
optimized for membrane protein purification, delipidation, and
individual applications in native mass spectrometry of
proteins.[10-11] Interestingly, [G1] OGD regioisomer mixtures can
extract larger protein quantities from membranes than individual
10c]
isomers.[10a,
So far, [G1] OGD mixtures have been
successfully applied for the purification of inner and outer
membrane proteins of Escherichia coli (E. coli) and a functional
neurotensin receptor 1 (NTSR1) – a member of the G-protein
coupled receptor family, which is currently one of the most
interesting protein classes in pharmacology.[12] However, the
synthesis and molecular properties of [G1] OGD regioisomer
mixtures have not yet been explored in full detail. Here, we
address this shortcoming by investigating (i) the general
synthesis of OGD regioisomer mixtures and (ii) the molecular
properties of individual [G1] OGD regioisomers to better
understand the utility of their mixtures for extracting large protein
quantities.
Results and Discussion
Acetal-protected, first-generation triglycerol [pG1]-OH is the
starting material for dendritic OGDs. It is synthesized by acetal
protection of oliglycerol mixtures (Figure 1).[13] Oligoglycerol
mixtures are heterogeneous. They contain different glycerol
oligomers and each oligomer population is divided into several
regioisomer populations. For triglycerol, seven regioisomers
exists and their relative abundances vary with the production
method (Figure S1).[14] The exact composition of oligoglycerol
mixtures therefore remains a black box. However, they serve as
a valuable resource for the synthesis of dendritic OGDs, as it
requires only one step to convert them into [pG1]-OH.[13]
Given the heterogeneity of oligoglycerol mixtures, we
investigated if triglycerol regioisomers are co-purified during
acetal protection (Figure 1). We screened oligoglycerol from
three individual batches and analysed the products by analytical
HPLC, electrospray ionization mass spectrometry (ESI-MS), and
NMR spectroscopy. Irrespective of the oligoglycerol batch, we
identified two products by HPLC (Figure S2, Table S1). The
exact masses of both products obtained from ESI-MS agreed
with those calculated from the sum formula of [pG1]-OH. Their
NMR data, however, showed clear differences (Figure S3). This
indicates that both products are regioisomers, which differ in
terms of the connectivity between glycerol units. Taking into
account previous reports on relative abundances of triglycerol
regioisomers,[14b] the co-purified regioisomers of [pG1]-OH are
likely those show in Figure 1 (a, b). Their absolute identity was
confirmed by synthesizing both isomers separately and
comparing their NMR data to those obtained from the products
isolated by HPLC (Figure S3). The relative abundances of a and
b as well as the overall product yields vary with the oligoglycerol
batch (Table S1).
Figure 1. Utility of oligoglycerol mixtures for the synthesis of [pG1]-OH. Two
regioisomers of [pG1]-OH (a and b) can be co-purified during acetal protection
of oligoglycerol mixtures and subsequent column purification.
To elucidate how the use of [pG1]-OH regioisomer mixtures is
affecting the heterogeneity of [pG2]-OH batches, we performed
this reaction on a [pG1]-OH regioisomer mixture (a:b, 6:4). For
the given reaction conditions, we assume that (i) only one
chlorine atom of methallyl dichloride is substituted at a time by a
or b and (ii) that the same applies to the formed intermediate
(Figure S4). Upon ozonolysis and reduction, we expected three
[pG2]-OH regioisomers, which differ in the structure of their
triglycerol side chains: aa, ab, and bb (Figure 2, Figure S4). To
prove the formation a regioisomer mixture, we synthesized aa
and bb separately. We compared their HPLC and NMR data to
those obtained from the proposed mixture containing aa, ab,
and bb. We were not able to distinguish between aa and the
proposed isomer mixture using normal-phase HPLC or 1H NMR
spectroscopy (Figure S5-6). Both methods may therefore not be
suitable to differentiate regioisomers of [pG2]-OH. In addition,
we analysed the 13C NMR spectra between 82 and 66 ppm.
This spectral region reflects a structural fingerprint of [pG2]-OH
regioisomers, as it is sensitive to variations in the triglycerol side
chains (Figure S6). The signals of aa and bb are well-
represented in the spectrum of the proposed isomer mixture,
which underlines that at least two regioisomers of [pG2]-OH
were formed. Surprisingly, the 13C NMR signals of the focal
points are sensitive to the structure of the triglycerol side chains
(Figure S6). The chemical shifts obtained from aa and bb
differed by less than one ppm. Both signals also appeared in the
spectrum of the proposed regioisomer mixture. Closer analysis
of the relative signal abundances revealed a regioisomer
stoichiometry of about 4:4:1 (aa:ab:bb, Table S2).
To synthesize the next generation [pG2]-OH, two
equivalents of [pG1]-OH are reacted with one equivalent of 3-
chloro-2-chloromethyl-1-propene (methallyl dichloride) under
basic conditions.[13] In order to finally yield [pG2]-OH, the double
bond at the focal point of the intermediate [pG2]-ene is
converted to a hydroxyl group via ozonolysis and reduction.[13]
2
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Figure 2. Synthesis of [G1] and [G2] OGD regioisomer mixtures. The use of a [pG1]-OH regioisomer mixture (a,b) as starting material leads to three [pG2]-OH
regioisomers (aa, ab, bb), which differ in terms of the structure of their triglycerol side chains. Using [pG1]-OH and [pG2]-OH regioisomer mixtures as starting
material for detergents leads to b) [G1] and c) [G2] OGD regioisomer mixtures (for further information see Supporting Information).
Both [pG1]-OH and [pG2]-OH are starting materials for dendritic
We obtained similar results for the [G2] OGD batches 5 – 6
(Table S2). However, we observed significant shift in
13, 15]
OGD architectures.[10a,
This motivated us to investigate
a
whether regioisomer ratios will change during detergent
synthesis. We applied standard protocols to synthesize the
[G1] OGD regioisomer mixtures 1 – 4, including direct alkylation
(1); mesylation followed by azidation, reductive amination, and
alkylation via amide coupling (2); propargylation and alkylation
via copper-catalysed click reaction (3); and mesylation followed
by alkylation (4).[10a, 10b, 13] Irrespective of the employed synthetic
strategy, regioisomer ratios of [G1] OGDs were similar to those
obtained in the starting material (a:b, 6:4, Figure 2, Table S2).
We therefore conclude that regioisomer ratios of [pG1]-OH can
be fully retained using the experimental conditions employed.
regioisomer ratios for the [G2] OGD batches 7, 8 and 9, which
indicates that the ability to retain regioisomer ratios of [pG2]-OH
varies with the applied synthesis strategy (Figure 2, Table S2).
Having established the synthesis and characterization of
OGD regioisomer mixtures, we investigated why [G1] OGD
regioisomers can extract more protein quantities from biological
membranes than individual regioisomers.[10a] Membranes exhibit
a hydrophobic core and a hydrophilic surface, which are formed
by a bilayer of lipid molecules. Protein-containing membranes
are poorly soluble in water and exhibit amphiphilic properties.
3
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Figure 3. The influence of individual [G1] OGD regioisomers on the interfacial surface tension (IFT) of a water droplet. a) Lower IFT values are obtained from
regioisomer 4b. b) Changing the focal point in 4b increases the length of the non-polar tail by one methylene unit and increases the size of the polar head group
as indicated by a larger collisional cross section (CCS). The [G1] regioisomer 4b is more hydrophobic than 4a although it exhibits a slightly larger polar head
group. CCS values were calculated from model structures using the projection approximation algorithm (for further information see Supporting Information).
Following the motto Similia similibus solvuntur! (Similar
substances will dissolve similar substances!), detergents can
break up membranes and solubilize both lipids and proteins by
forming water-soluble aggregates. The mechanisms with which
detergents extract membrane proteins from membranes has
been studied extensively.[16] However, the origin of the unusual
utility of [G1] OGD regioisomers for extracting large protein
quantities from membranes remains puzzling.
phase HPLC column material. The retention times of the
isomers 1a, 2a, and 3a were consistently shorter, thus pointing
to a less efficient interaction with the hydrophobic stationary
phase (Figure S7). This underlines that symmetric [G1] OGD
regioisomers 1a, 2a, and 3a indeed exhibit an less hydrophobic
character, irrespective of the linker between head and tail.
Second, we investigated if the change in hydrophobicity is
affecting the aggregation behaviour. For this purpose, we
determined the critical aggregation concentration (cac) for 3, 3a,
and 3b by means of dynamic light scattering.[20] The cac of 3a
(470 µM) is higher than that of 3b (390 µM), which agrees with
its reduced hydrophobicity. Moreover, the cac of the mixture 3
(550 µM) is higher than the cac values of the individual isomers
3a and 3b. A similar trend was observed among the regioisomer
mixture 1 (700 µM) and the individual isomer 1a (490 µM). This
indicates that increasing the heterogeneity in [G1] OGD
detergent mixtures lowers their tendency to form detergent
aggregates.
To study the relevance of the outlined property differences
for membrane protein purification, we re-investigated the utility
of [G1] OGD regioisomers 3a and 3b to extract the aquaporin
channel (AqpZ) and ammonia channel (AmtB) from native
membranes of E. coli.[10a] The protein quantities were normalized
to those obtained from n-dodecyl-ß-D-maltoside (DDM), which is
a standard detergent in structural biology.[21] Lower protein
quantities were obtained from the regioisomer 3b (Figure 4,
Figure S8). This agrees with the hypothesis that increasing the
length of the tail as well as the size of the head group decreases
the ability of OGDs to solubilize biological membranes.[10a] In
contrast, higher protein yields were obtained from the [G1] OGD
regioisomer mixture 3. We assume that mixing detergents with
slightly different hydrophobic tails and head groups provides a
better mimic for heterogeneous lipid membranes than
monodisperse detergent batches. Moreover, the reduced
propensity of [G1] OGD regioisomer mixtures to form detergent
aggregates leads likely to a higher concentration of detergent
monomers in solution.[22] This could support protein extraction,
because the uptake of detergent monomers into membranes is a
potential key step for initializing membrane solubilization.[23]
The utility of a detergent for protein extraction depends on its
17]
molecular structure.[10a,
This motivated us to study the
molecular properties of individual [G1] OGD regioisomers in
more detail using the pendant drop method. The air surrounding
a water droplet is hydrophobic and water is hydrophilic. The
lateral polarity distribution of the air-water interface is similar to
that of a membrane. Detergents adsorb at the air-water interface
and reduce the interfacial surface tension (IFT).[18] Lower IFT
values were obtained for 4b, which indicates that its structure is
more hydrophobic than 4a (Figure 3).[19] This agrees with the
observation that the change of the focal point in 4b increases
the length of the hydrophobic tail effectively by the length of one
methylene unit. At the same time, collision cross section (CCS)
values calculated from model structures suggest that the
difference in focal point structure also increases the size of the
head of 4b (Figure 3). Increasing the size of the hydrophilic head
group usually decreases the hydrophobicity of a dendritic
OGD.[10a] However, the opposite seems to be the case for [G1]
OGD regioisomers.
An alternative measure for the hydrophobicity of organic
compounds is the partition coefficient (P), which is defined as a
ratio of concentrations of a solute between two solvents. Given
that one solvent is water and the other a non-polar solvent, the
logarithm of P (logP) becomes a measure of hydrophobicity.
Conversely, the logP values predicted by ChemDraw for both
isomers are similar (example: logP of 1a and 1b = 2.23). This
led to the question whether the differences in hydrophobicity
indicated by surface tension experiments are relevant for
solution properties of [G1] OGDs.
To address this question, we first compared the isocratic
elution profiles of [G1] OGD regioisomer mixtures from reversed-
4
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Figure 4. Utility of [G1] OGDs for purifying membrane proteins. (a) Increasing the size of the head and length of the tail among 3a and 3b reduces achievable
protein yields. Higher protein yields were obtained from the [G1] OGD regioisomer mixture 3. (b) The proteolytic activity of OmpT against a self-quenching,
fluorescent peptide is not strongly affected by the presence or absence of [G1] OGD regioisomer 1b. Mixing detergents with slightly different hydrophobic tails and
head groups may not affect protein activity but provides a better mimic for heterogeneous lipid membranes during extraction.
Previous detergent exchange experiments on the outer
membrane protein F revealed that [G1] OGD regioisomer
mixtures and individual regioisomers can form stable
proteomicelles in the absence of membranes.[10a] Considering
these results, we finally investigated if mixing [G1] OGD
regioisomers can affect the activity of membrane proteins. The
outer membrane protease T (OmpT) was selected as model
system, because it is compatible to [G1] OGDs.[10a] Briefly, the
protein was isolated from inclusion bodies of E. coli and refolded
using the [G1] OGD regioisomer mixture 1. Refolded OmpT was
incubated with the self-quenching, fluorescent peptide and
lipopolysaccharide (LPS). Binding to LPS is required to increase
the proteolytic activity of OmpT.[24] The digestion of the self-
quenching peptide by OmpT produces a fluorescent peptide
fragment. Therefore, the activity of OmpT could be monitored by
utility of detergent mixtures for extracting large protein quantities
from membranes. We anticipate that heterogeneous, lipid-like
detergent mixtures will facilitate the extraction and analysis of
difficult membrane proteins in the future.
Experimental Section
Details about the synthesis and experiments are provided in the
Supporting Information. NMR raw data can be downloaded from
the OSF website (https://doi.org/10.17605/OSF.IO/TJXSR). The
synthesis protocols of [G1] OGD batches 1, 3, and [G2] OGD
batches 5, 8, and 9 have been reported previously.[10a, 10b] The
protocols for the synthesis of 2, 4, 6, and 7 have not been
published before.
fluorescence spectroscopy in
a
time-resolved manner
25]
(Figure 4).[10a,
Control experiments with the individual
regioisomer 1a revealed that the proteolytic activity is not
significantly affected by the absence of regioisomer 1b.
Conflict of Interest
The authors declare no conflict of interest.
Conclusion
Acknowledgements
In summary, we investigated the synthesis of oligoglycerol
regioisomer mixtures. We found that triglycerol regioisomers are
co-purified during acetal protection of oligoglycerol mixtures. The
ability to retain regioisomer ratios during detergent synthesis
varies with the dendron generation and synthesis strategy. The
NMR raw data provided with this paper will facilitate a better
quality control of dendritic detergents after synthesis. Both
[G1] OGD regioisomers and individual isomers can form stable
proteomicelles and retain the activity of membrane proteins in
the absence of membranes. However, changing the focal point
structure in [G1] OGD regioisomers simultaneously increases
the size of the head and overall hydrophobicity of the detergent,
thus leading to a more lipid-like environment in their mixtures.
Furthermore, aggregates formed by [G1] OGD regioisomer
mixtures may co-exist with a larger population of detergent
monomers in solution compared to aggregates formed by
individual isomers. These unusual properties are linked with the
Funding was provided by the Focus Area Nanoscale of the Freie
Universität Berlin, Fonds der Chemischen Industrie (FCI), and
ERC Advanced Grant No. 695511 (ENABLE). The authors
acknowledge J. R. Bolla, P. Winchester, C. Fasting, V. Wycisk,
M. Wyszogrodzka, and the Core Facility BioSupraMol of the
Freie Universität Berlin for continuous support.
Keywords: dendron • oligoglycerol • detergent • regioisomer •
membrane protein purification
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Entry for the Table of Contents
The secret lies in the mix: Regioisomer mixtures of dendritic oligoglycerol detergents have recently attracted attention from
experimentalist in membrane protein research. The present study outlines the synthesis of detergent regioisomer mixtures and sheds
light on their utility for the purification of membrane proteins. The obtained results point to new avenues for the development of
lipid-like detergent mixtures in membrane protein research.
Institute and/or researcher Twitter usernames: @pagelgroup, @fubcp
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