Designing Mixed Detergent Micelles for Uniform Neutron Contrast

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Letter

Designing Mixed Detergent Micelles for Uniform Neutron Contrast Ryan C Oliver, Sai Venkatesh Pingali, and Volker S. Urban J. Phys. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acs.jpclett.7b02149 • Publication Date (Web): 29 Sep 2017 Downloaded from http://pubs.acs.org on October 1, 2017

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The Journal of Physical Chemistry Letters

Designing Mixed Detergent Micelles for Uniform Neutron Contrast Ryan C. Oliver, Sai Venkatesh Pingali, Volker S. Urban* Center for Structural Molecular Biology and Biology and Soft Matter Division; Oak Ridge National Laboratory; P.O. Box 2008, MS 6430; Oak Ridge, Tennessee 37831, United States This manuscript has been authored by UT-Battelle, LLC under Contract No. DE-AC0500OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (http://energy.gov/downloads/doe-public-access-plan).

Corresponding Author * Email: [email protected]. Phone: +1 865-576-7221. Fax: +1 865-574-6080.

1 ACS Paragon Plus Environment


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Abstract. Micelle-forming detergents provide an amphipathic environment that mimics lipid bilayers and are important tools used to solubilize and stabilize membrane proteins in solution for in vitro structural investigations. Small-angle neutron scattering (SANS) at the neutron contrast match point of detergent molecules allows observing the signal from membrane proteins unobstructed by contributions from the detergent. However, we show that even for a perfectly average-contrast matched detergent there arises significant core-shell scattering from the contrast difference between aliphatic detergent tails and hydrophilic head groups. This residual signal interferes with interpreting structural data of membrane proteins. This complication is often made worse by the presence of excess empty (protein-free) micelles. We present an approach for the rational design of mixed micelles containing a deuterated detergent analog, which eliminates neutron contrast between core and shell, and allows the micelle scattering to be fully contrast matched to unambiguously resolve membrane protein structure using solution SANS.


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Detergent micelles represent the most commonly employed type of membrane mimic used to solubilize membrane proteins in aqueous solutions for in vitro structural and functional investigations, and have demonstrated many successes.1-5 Numerous detergents have been synthesized in recent decades with a wide variety of chemical and physical properties designed to mimic features of native membranes.6-10 This variety provides a broad spectrum of tenable micelle conditions formed from one or more of these detergents.11 The recent commercial availability of deuterium-labelled detergents, such as dodecyl maltoside (DDM) with a fully deuterated alkyl chain (d25-DDM), has already proven beneficial (e.g. in structural investigations of protein-detergent complexes with solution NMR12), but these emerging detergents also have much to offer with regards to contrast matching micellar contributions in SANS experiments. The goal of a typical contrast matching SANS experiment is to obtain structural information for a single component of an assembled complex in solution. This process is generally achieved by altering the isotopic composition of the solvent (and/or parts of the complex) such that all parts except for the component of interest possess the same scattering length density (SLD) as the solvent.13 A subunit that has the same SLD as the solvent is said to be “contrast-matched”. Thus, if one desired to measure structural information about a membrane protein in a proteindetergent complex using SANS, then scattering contributions from aggregate detergent must be contrast-matched in order to obtain scattering information from only the protein. However, a detergent micelle itself contains two components – a shell formed by the detergent head groups and a core of alkyl chain tails – each with a unique SLD, and therefore different contrast match points.14 The following investigation provides a framework for removing detergent contributions in future SANS experiments by eliminating the contrast between micelle core and shell,



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permitting the micelle to be fully contrast-matched. This approach is particularly useful at high detergent concentrations and when significant difference in contrast between micelle core and shell exists. We have recently applied this method to extract the solution structure of a 31 kDa intramembrane aspartyl protease.15 The technique could also be extended to other applications of detergents in neutron scattering, such as dispersants16 and emulsion polymerization17, or applied to other core-shell systems such as some micelle-forming triblock copolymers.18 Neutron contrast calculations were performed using MULCh: ModULes For The Analysis Of Contrast Variation Data (http://smb-research.smb.usyd.edu.au/NCVWeb)19 to simulate scattering length densities (SLDs) of the outer shell formed by detergent head groups, the inner core formed by detergent alkyl chain tails, and the total scattering length density of the micelle. For micelles composed of DDM-only, the alkyl chains form a core that is contrast-matched in 2% D2O, while the maltose-like head groups form a shell contrast-matched in 49% D2O. The calculated total match point for a DDM micelle occurs in buffer containing approx. 22% D2O, consistent with previous values from the literature.14,20 These match points are represented by intersections with the solvent line in a plot of SLDs vs. fraction of D2O in the solvent (Figure 1). It is important to note that the individual match points of head and tail groups are far from the average match point of DDM micelles.


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Figure 1. Calculated scattering length densities plotted versus fraction of D2O in the solvent for DDM micelles (solid green and dashed lines) and mixed micelles of d25-DDM and DDM (solid lines). The SLD of the solvent is shown by the blue line. Intersections with the solvent line represent contrast match points. Our objective for this series of experiments was to create a mixed micelle using a blend of natural DDM and d25-DDM containing deuterated alkyl chain tails, such that both the micelle core and shell (and thus their average) have the same SLD at the solvent-matched condition. This condition is described by the solid lines in Figure 1, and their combined single-point intersection with the solvent. To accomplish this goal, the ratio of mixing was sought between DDM with either deuterated or hydrogenated tails that produced an average SLD equal to the detergent’s head groups. [NB: This approach relies on the two detergents (DDM and d25-DDM) being homogenously and evenly distributed at sufficient concentration throughout the micellar aggregate, such that the observed scattering reflects ideal mixing of DDM and d25-DDM.] A mixed micelle containing 43 molar percent of d25-DDM was determined to have an average core scattering length density, matching that of the head group shell and 49% D2O in the solvent. The percent by mole of d25-DDM required (Xd25-DDM) was determined from the relationship: SLDDDM-head = (1-Xd25-DDM) * SLDDDM-tail + Xd25-DDM * SLDd25-DDM-tail

(1)

Contrast values obtained from MULCh for each detergent component are summarized in Table 1. Calculations were also performed for mixtures of Fos-Choline 12 (FC12) or octyl glucoside (OG) detergents, both having commercially available counterparts with deuterated tails, as well as a ternary mixture incorporating perdeuterated (head and tail) d39-DDM. Unfortunately, d39DDM remains commercially unavailable at time of publication although its synthesis has been



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published.22 The results and predicted match points for these surfactant systems are described in the Supplemental Information – Neutron Contrast Determination (Table S1). Table 1. Physical constants and contrast match points from MULCh for DDM components. component

compositiona

MW

Vb

match point

(g mol-1)

(Å3)

(% D2O)

DDM

C24H39X7O11

510.6

698

22

Tail

C12H25

169.3

350

2

Head

C12H14X7O11

341.3

348

49

d25-DDM

C24H14X7D25O11

535.8

698*

86

Tail (deut.)

C12D25

194.5

350*

114

Head

C12H14X7O11

341.3

348

49

a

Solvent exchangeable hydrogen positions are indicated by an ‘X’ in the chemical formulae. Tail volumes calculated according to Tanford’s formula21 (27.4 + 26.9nC) where nC is the number of alkyl chain tail carbons. *Substitution of deuterium for hydrogen in the alkyl chain tail has negligible effect on the molecular volume.

b

SANS contrast series were collected for DDM micelles and the mixed d25-DDM / DDM micelle system (Figure 2). Each contrast series was used to determine an experimental total match point for the micelle solutions, and then collect scattering profiles at this total match point (Figure 2, shown in yellow) for further evaluation.


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Figure 2. Contrast variation SANS data. Recorded scattering intensities plotted as a function of the scattering angle, Q, for each contrast condition given by the concentration of D2O in the buffer for A) DDM micelles and B) mixed d25-DDM / DDM micelles containing 43% (by mole) deuterated alkyl chain tails. Simultaneous model fits to the data are shown as solid lines. Data collected at contrast match points shown in yellow. Extrapolation of linear fits to Q = 0 from a Guinier plot of the scattering data allowed the forward scattering intensity, I(0), to be determined for each sample in the contrast series (Figure S1, Supplemental Information – Neutron Contrast Determination). A plot of the square root of forward scattering intensities as a function of the fraction of D2O in the buffer forms a straight line (using negative values above the match point), where the x-intercept represents the total solution match point (Figure S1). This x-intercept for the DDM-only system occurs at 22% D2O in the buffer, in exact agreement with the predicted value from MULCh.



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Table 2. Table of results from Guinier fit analysis of SANS contrast series. DDM series

d25-DDM / DDM series

D2O

Q2-range

I(0)

Rg

D2O

Q2-range

I(0)

Rg

(%)

(10-3 Å-2)

(cm-1)

(Å)

(%)

(10-3 Å-2)

(cm-1)

(Å)

0

0.10-1.8

0.157 ±0.003

28.1 ±1.1

0

0.06-2.7

0.710 ±0.007

22.9 ±0.4

35

0.15-9.6

0.045 ±0.001

12.7 ±0.7

22

0.06-2.7

0.245 ±0.003

23.2 ±0.5

49

0.15-4.7

0.207 ±0.001

18.3 ±0.2

35

0.06-2.7

0.073 ±0.002

23.1 ±1.0

80

0.07-3.2

1.143 ±0.003

21.0 ±0.1

65

0.06-2.7

0.087 ±0.002

22.0 ±0.8

100

0.07-3.2

1.891 ±0.005

22.1 ±0.1

80

0.06-2.7

0.316 ±0.002

22.8 ±0.3

100

0.06-2.7

0.810 ±0.003

23.3 ±0.2

The forward scattering intensities [I(0)] and radii of gyration [Rg] determined from Guinier analysis are summarized in Table 2. The Rg is the root-mean-square average distance of the scattering centers (atoms) in the particle from the particle’s center-of-mass. This average is weighted by the contrast of scattering centers relative to the background medium (solvent). In the case of the DDM micelles, the 0% D2O sample was very near to the contrast match point of the DDM core at 2% D2O, and thus the observed scattering was primarily contributed by the micellar shell structure. This ‘hollow sphere’ structure is reflected by the largest Rg (28.1 Å). Similarly, the sample in 49% D2O contained contrast-matched head groups with its scattering contributed primarily by the micelle core, thus a smaller Rg (18.3 Å) was observed. The fact that the relative contributions from different parts of the micelle vary depending on contrast, is


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clearly reflected in the change of the overall shape of the scattering curves throughout the contrast series (Figure 2A). Although the physical properties of the d25-DDM / DDM mixed micelles remain unchanged compared to micelles of DDM, significant changes in their neutron scattering signal are observed. Most notably, the total contrast match point increased from 22 to 49% D2O for the mixed micelle system. In addition, the shape of the scattering profiles is very similar for all d25DDM / DDM mixed micelles at all contrast conditions unlike observed for DDM. This information reflects the absence of any observable core-shell contrast. Thus, the approach of contrast matching between core and shell was successful. Importantly, this observation implies that the deuterated and non-deuterated tails of the surfactant molecules mix randomly to form an ideally mixed micelle with uniform scattering length density. However, the total match point of the detergent at 49% D2O is near to the typical match point for an unlabeled protein (~42% D2O), suggesting that a protein must be deuterium-labeled to achieve sufficient contrast in this mixed detergent system. This deuterium-labelling approach23 has been successfully reported for systems containing membrane proteins, as demonstrated recently for monitoring conformational changes of receptor-binding protein pb5 bound to the membrane protein receptor FhuA using a specialized fluorinated surfactant, F6-DigluM, also possessing a neutron contrast-matched micelle core and shell.24 The Rg calculated from Guinier analysis of the mixed micelle system (Table 2) is near 23 Å (within error) at all contrast conditions. This result also reflects a uniform observed structure and therefore uniform scattering contrast. All measurements of these particles at different solvent contrasts revealed a similar size and shape. Our final assessment of the mixed micelle system relied on its ability to be fully contrast matched at the total contrast match point. For DDM, the 9 ACS Paragon Plus Environment


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I(0) at this condition approaches zero, as is expected for average-matched scattering in the forward direction where scattering amplitudes from all parts of the micelle interfere in phase. On the other hand, the scattering profile shows a broad peak at Qmax ≈ 0.14 Å-1 because of the coreshell micelle structure (Figure 3). In analogy to Bragg diffraction, the position of this maximum reflects distances between scattering elements of the shell and therefore provides an estimate of the micelle diameter as: D ≈ 2π/Qmax = 45 Å.10 For the mixed DDM / d25-DDM micelle, the net forward scattering approaches zero and the scattering profile remained flat over the Q-range measured. Thus, for these mixed micelles measured at their contrast match point, detergent contributions were negligible, and therefore not expected to interfere with SANS measurements from a deuterated membrane protein in a protein-detergent complex with a contrast-matched detergent system.

Figure 3. Comparison of the micelle scattering signal at the total match point of each solution shown as a linear-linear plot (same data shown in yellow of Figure 2). A linear fit to the flat scattering profile observed for the mixed micelle and a Gaussian fit to the peak corresponding to the core-shell structure of the DDM-only micelles has been added to guide the eye. Additional details of size and shape for the DDM and mixed d25-DDM / DDM micelles were obtained by model fitting of the full range of measured SANS data. Simultaneous fits were 10 ACS Paragon Plus Environment

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performed for all contrast values (Figure 2), except for the contrast match point due to the general absence of scattering information at this condition. Core-shell oblate ellipsoid of revolution models were used for micelles composed of only non-deuterated DDM, where the SLD of the core and shell is not equal. The overall size of DDM micelles from simultaneous fits of the contrast series is described by a core polar radius of 14.4 ±0.9 Å, a core equatorial radius of 27.4 ±1.0 Å and a shell thickness of 6.7 ±1.0 Å. The d25-DDM / DDM series, on the other hand, was fit to a solid oblate ellipsoid of revolution model. For these mixed micelles, the polar radius was determined to be 19.7 ±0.6 Å with an equatorial radius of 33.1 ±0.5 Å. These values are in excellent agreement with the DDM core-shell model, noting that the shell thickness needs to be added to the core radii to arrive at the solid ellipsoid radii values for the mixed system. Importantly, incorporation of deuterated tails does not appear to significantly impact the overall micelle structure and packing. These structural results are furthermore consistent with similar values from previous small-angle X-ray scattering measurements for DDM micelles of 21.5 ±0.4 Å and 33.7 ±0.4 Å, for the polar and equatorial radii (including the shell thickness), respectively.10 Detergent concentration and buffer conditions, differences between the two scattering probes used, or the presence of the α-anomer at up to 15% (compared to the low-α DDM used in other studies) may contribute to these minor observed differences between the present SANS study and earlier X-ray results.25 Detergent micelle shapes have been recently debated in the literature26-29 and for completeness we include in our analysis a comparison between ellipsoid and sphere models (Figure S2, Supplemental Information – Models). The improvement relative to a sphere model is in χ2 from 13.5 to 1.6 for the core-shell model and 4.1 to 1.2 for the solid ellipsoid model. This reduction in χ2 stems from an improvement in the fit around Q ≈ 0.2 Å-1, near the location of the first



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oscillation in the spherical fit. Thus the ellipsoid model provides a significantly better fit, in addition to having a physical basis that accounts for packing geometry and the ability of the micelle to contain the required aggregation number of monomers without significant energetic penalties from mismatched head groups or formation of a central void in the micelle.26,30-34 Notably, the core-shell structure of the DDM micelle is more sensitive to the difference in fit quality between ellipsoid and sphere models, and we point out that measuring both contrast situations enhances the confidence with which the ellipsoid model can be considered superior to a spherical model. This investigation demonstrates that partially deuterated dodecyl maltoside micelles were successfully constructed with their inherent core-shell contrast eliminated. These micelles produce a fully contrast-matched and flat SANS profile when measured at their contrast match point. Additionally, the incorporation of deuterated tails does not have a significant impact on the resulting micelle size and shape as compared to micelles of only non-deuterated DDM. This work provides a maltoside detergent-based example of how contrast matching can be improved to remove scattering contributions from the detergent components in neutron scattering studies. Experimental Methods. The detergents n-dodecyl-β-d-maltopyranoside (DDM) and ndodecyl-d25-β-d-maltopyranoside (d25-DDM) were obtained from Anatrace. The deuterated-tail analog of the detergent (d25-DDM) contains up to 15% of the α-anomer, therefore natural DDM also containing up to 15% of the α-anomer was used throughout this investigation. Anomeric effects on the structure of DDM micelles in water have previously been reported.25 Deuterium oxide (D2O) and all other chemicals were obtained from Sigma. The total detergent concentration for all samples was 20 mM, or 1.0% by weight. Mixed micelles contained d25DDM as 43% by mole (or 44% by weight) of the total detergent, with DDM as the remainder. 12 ACS Paragon Plus Environment

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Additionally, all samples were buffered with 20 mM HEPES and 250 mM NaCl, at pH 7.5 in differing ratios of D2O/H2O. SANS data were collected at the Bio-SANS beam line (CG3) of the High-Flux Isotope Reactor at Oak Ridge National Laboratory (Oak Ridge, TN) using a single 7m instrument configuration. Data were collected at 25ºC using 1mm quartz cells and neutron wavelength of 6 Å ±13%. The useable range of momentum transfer Q was 0.007 < Q < 0.9 Å-1 (Q = 4π·sin(θ)/λ, where 2θ is the scattering angle and λ is the neutron wavelength). Additional descriptions of the instrument and setup have been previously published.35-37 The recorded scattering data were circularly averaged, and reduced to 1D scattering profiles using MantidPlot software.38 Blank buffers containing the same % D2O as the samples were similarly measured and subtracted from the sample scattering for background correction. Guinier analysis was performed using an analysis toolkit developed by Dr. Ken Littrell (ORNL) in IgorPro software (WaveMetrics, Lake Oswego, OR), and also using ATSAS software.39



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ASSOCIATED CONTENT Supporting Information. Additional descriptions of the methods used and additional model fits to each scattering profile, their descriptions, and residuals of fits, are included as supplemental material. This information is available free of charge via the Internet at http://pubs.acs.org. The following files are available free of charge: Supplemental Information – Methods (PDF) Supplemental Information – Models (PDF) Notes The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. The authors declare no competing financial interests.

ACKNOWLEDGMENT Neutron scattering studies at the CG-3 Bio-SANS instrument at the High-Flux Isotope Reactor of Oak Ridge National Laboratory were sponsored by the Office of Biological and Environmental Research and by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy. This work benefited from the use of the SasView application, originally developed under NSF award DMR-0520547. SasView contains code developed with funding from the European Union’s Horizon 2020 research and innovation programme under the SINE2020 project, grant agreement No 654000. REFERENCES (1) Zhou, H. X.; Cross, T. A., Influences of Membrane Mimetic Environments on Membrane Protein Structures. Annu. Rev. Biophys. 2013, 42, 361-392.


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(11) Oliver, R. C.; Lipfert, J.; Fox, D. A.; Lo, R. H.; Kim, J. J.; Doniach, S.; Columbus, L., Tuning Micelle Dimensions and Properties with Binary Surfactant Mixtures. Langmuir 2014, 30 (44), 13353-13361. (12) Hiruma-Shimizu, K.; Shimizu, H.; Thompson, G. S.; Kalverda, A. P.; Patching, S. G., Deuterated Detergents for Structural and Functional Studies of Membrane Proteins: Properties, Chemical Synthesis and Applications. Mol. Membr. Biol. 2015, 32 (5-8), 139-155. (13) Jacques, D. A.; Trewhella, J., Small-angle Scattering for Structural Biology-Expanding the Frontier while Avoiding the Pitfalls. Protein Sci. 2010, 19 (4), 642-657. (14) Breyton, C.; Gabel, F.; Lethier, M.; Flayhan, A.; Durand, G.; Jault, J. M.; Juillan-Binard, C.; Imbert, L.; Moulin, M.; Ravaud, S.; Hartlein, M.; Ebel, C., Small Angle Neutron Scattering for the Study of Solubilised Membrane Proteins. Eur. Phys. J. E 2013, 36 (71). DOI: 10.1140/epje/i2013-13071-6. (15) Naing, S. H.; Oliver, R. C.; Weiss, K. L.; Urban, V. S.; Lieberman, R. L., Solution Structure of an Intramembrane Aspartyl Protease Determined by Small Angle Neutron Scattering [working title], to be submitted for publication in Oct 2017. (16) Galsworthy, J.; Hammond, S.; Hone, D., Oil-soluble Colloidal Additives. Curr. Opin. Colloid Interface Sci. 2000, 5(5), 274-279. (17) Fowler, C. I.; Muchemu, C. M.; Miller, R. E.; Phan, L.; O’Neill, C.; Jessop, P. G.; Cunningham, M. F., Emulsion Polymerization of Styrene and Methyl Methacrylate Using Cationic Switchable Surfactants. Macromolecules. 2011, 44(8), 2501-2509. (18) Wang, H.; Wang, H. H.; Urban, V. S.; Littrell, K. C.; Thiyagarajan, P.; Yu, L., Syntheses of Amphiphilic Diblock Copolymers Containing a Conjugated Block and Their Self-Assembling Properties. JACS. 2000, 122(29), 6855-6861.


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