Structure of Diisobutylene Maleic Acid Copolymer (DIBMA) and Its Lipid Particle as a “Stealth” Membrane-Mimetic for Membrane Protein Research

Guo, Rong; Sumner, Jacob; Qian, Shuo

doi:10.1021/acsabm.0c01626

Structure of Diisobutylene Maleic Acid Copolymer (DIBMA) and Its Lipid Particle as a “Stealth” Membrane-Mimetic for Membrane Protein Research

Journal Article · Tue Apr 06 00:00:00 EDT 2021 · ACS Applied Bio Materials

DOI:https://doi.org/10.1021/acsabm.0c01626· OSTI ID:1807315

Guo, Rong ^[1]; Sumner, Jacob ^[2]; ^[2]

Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Grinnell College, IA (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

The study of membrane proteins remains challenging, especially in a native membrane environment. Recently, major progress has been made using maleic acid copolymers, such as styrene maleic acid, to purify membrane proteins and study them directly with native lipids associated with the membrane. Additional maleic acid copolymers, such as diisobutylene maleic acid (DIBMA) membrane-mimetic systems, are being developed and found to have improved spectroscopic properties and pH stability. We studied DIBMA and its lipid particles in solution to better understand its assembly, without and with the lipids, to provide an insight regarding how to use it in solution for better membrane extraction. Using small-angle neutron and X-ray scattering (SANS/SAXS), we show that DIBMA organizes into structures of different size scales at various concentrations and ionic strengths. The polymer performed reasonably well under most solvent conditions except in very low concentrations and high-salt conditions that could result in limited interaction with lipids. To explore DIBMA lipid particles as a suitable membrane-mimetic system for neutron scattering studies of membrane proteins, we measured and determined the contrast-matching point of DIBMA to be ~12% (v/v) D₂O — similar to that of most protiated lipid molecules but distinct from that of regular protiated proteins — providing a natural contrast for separating their neutron scattering signals. Using SANS contrast variation, we demonstrated that the scattering from the whole lipid particle can be annihilated. Further, we determined that a well-defined lipid nanodisc structure with DIBMA was contrast-matched. These results demonstrate that the DIBMA lipid particle is an outstanding “stealth” membrane-mimetic for membrane proteins. The results provide a structural framework for understanding the organization and assembly process of the polymer itself and the lipid molecules. Such an understanding is imperative for structural techniques such as cryo-electron microscopy, nuclear magnetic resonance, small-angle scattering, and other biophysical techniques.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1807315

Alternate ID(s):: OSTI ID: 1814975
OSTI ID: 1819355

Journal Information:: ACS Applied Bio Materials, Journal Name: ACS Applied Bio Materials Journal Issue: 6 Vol. 4; ISSN 2576-6422

Publisher:: ACS PublicationsCopyright Statement

Country of Publication:: United States

Language:: English

References (54)

Detergent-Free Formation and Physicochemical Characterization of Nanosized Lipid-Polymer Complexes: Lipodisq Orwick, Marcella C.; Judge, Peter J.; Procek, Jan Angewandte Chemie International Edition, Vol. 51, Issue 19 https://doi.org/10.1002/anie.201201355	journal	March 2012
Solubilization of Membrane Proteins into Functional Lipid-Bilayer Nanodiscs Using a Diisobutylene/Maleic Acid Copolymer Oluwole, Abraham Olusegun; Danielczak, Bartholomäus; Meister, Annette Angewandte Chemie International Edition, Vol. 56, Issue 7 https://doi.org/10.1002/anie.201610778	journal	January 2017
Interrogating Membrane Protein Conformational Dynamics within Native Lipid Compositions Reading, Eamonn; Hall, Zoe; Martens, Chloe Angewandte Chemie International Edition, Vol. 56, Issue 49 https://doi.org/10.1002/anie.201709657	journal	November 2017
NMR Perspectives of the KcsA Potassium Channel in the Membrane Environment Chill, Jordan H.; Qasim, Arwa; Sher, Inbal Israel Journal of Chemistry, Vol. 59, Issue 11-12 https://doi.org/10.1002/ijch.201900107	journal	August 2019
Synthesis, Characterization and Applications of a Perdeuterated Amphipol Giusti, Fabrice; Rieger, Jutta; Catoire, Laurent J. The Journal of Membrane Biology, Vol. 247, Issue 9-10 https://doi.org/10.1007/s00232-014-9656-x	journal	October 2014
The styrene–maleic acid copolymer: a versatile tool in membrane research Dörr, Jonas M.; Scheidelaar, Stefan; Koorengevel, Martijn C. European Biophysics Journal, Vol. 45, Issue 1 https://doi.org/10.1007/s00249-015-1093-y	journal	December 2015
Structural studies of complex systems using small-angle scattering: a unified Guinier/power-law approach Beaucage, G.; Schaefer, D. W. Journal of Non-Crystalline Solids, Vol. 172-174 https://doi.org/10.1016/0022-3093(94)90581-9	journal	September 1994
Analysis of the solution structure of Thermosynechococcus elongatus photosystem I in n-dodecyl-β-d-maltoside using small-angle neutron scattering and molecular dynamics simulation Le, Rosemary K.; Harris, Bradley J.; Iwuchukwu, Ifeyinwa J. Archives of Biochemistry and Biophysics, Vol. 550-551 https://doi.org/10.1016/j.abb.2014.04.005	journal	May 2014
Molecular structures of fluid phase phosphatidylglycerol bilayers as determined by small angle neutron and X-ray scattering Pan, Jianjun; Heberle, Frederick A.; Tristram-Nagle, Stephanie Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1818, Issue 9 https://doi.org/10.1016/j.bbamem.2012.05.007	journal	September 2012
Detergent-free extraction of a functional low-expressing GPCR from a human cell line Bada Juarez, Juan Francisco; Muñoz-García, Juan C.; Inácio dos Reis, Rosana Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1862, Issue 3 https://doi.org/10.1016/j.bbamem.2019.183152	journal	March 2020
Lipid dynamics in nanoparticles formed by maleic acid-containing copolymers: EPR spectroscopy and molecular dynamics simulations Colbasevici, Alexandr; Voskoboynikova, Natalia; Orekhov, Philipp S. Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1862, Issue 5 https://doi.org/10.1016/j.bbamem.2020.183207	journal	May 2020
Effects of charged lipids on the physicochemical and biological properties of lipid–styrene maleic acid copolymer discoidal particles Tanaka, Masafumi; Miyake, Hisayasu; Oka, Satoko Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1862, Issue 5 https://doi.org/10.1016/j.bbamem.2020.183209	journal	May 2020
A comparison of SMA (styrene maleic acid) and DIBMA (di-isobutylene maleic acid) for membrane protein purification Gulamhussein, Aiman A.; Uddin, Romez; Tighe, Brian J. Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1862, Issue 7 https://doi.org/10.1016/j.bbamem.2020.183281	journal	July 2020
DIBMA nanodiscs keep α-synuclein folded Adão, Regina; Cruz, Pedro F.; Vaz, Daniela C. Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1862, Issue 9 https://doi.org/10.1016/j.bbamem.2020.183314	journal	September 2020
Complexity of seemingly simple lipid nanodiscs Stepien, Piotr; Augustyn, Bozena; Poojari, Chetan Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1862, Issue 11 https://doi.org/10.1016/j.bbamem.2020.183420	journal	November 2020
Effect of Polymer Composition and pH on Membrane Solubilization by Styrene-Maleic Acid Copolymers Scheidelaar, Stefan; Koorengevel, Martijn C.; van Walree, Cornelius A. Biophysical Journal, Vol. 111, Issue 9 https://doi.org/10.1016/j.bpj.2016.09.025	journal	November 2016
PSI-SMALP, a Detergent-free Cyanobacterial Photosystem I, Reveals Faster Femtosecond Photochemistry Cherepanov, Dmitry A.; Brady, Nathan G.; Shelaev, Ivan V. Biophysical Journal, Vol. 118, Issue 2 https://doi.org/10.1016/j.bpj.2019.11.3391	journal	January 2020
Influence of Mg2+ and Ca2+ on nanodisc formation by diisobutylene/maleic acid (DIBMA) copolymer Danielczak, Bartholomäus; Meister, Annette; Keller, Sandro Chemistry and Physics of Lipids, Vol. 221 https://doi.org/10.1016/j.chemphyslip.2019.03.004	journal	July 2019
Analysis of styrene maleic acid alternating copolymer supramolecular assemblies in solution by small angle X-ray scattering Brady, Nathan G.; Qian, Shuo; Bruce, Barry D. European Polymer Journal, Vol. 111 https://doi.org/10.1016/j.eurpolymj.2018.11.034	journal	February 2019
Structural analysis of dendrimers based on polyhedral oligomeric silsesquioxane and their assemblies in solution by small-angle neutron scattering: Fits to a modified two correlation lengths model Yuan, Guangcui; Wang, Xing; Wu, Decheng Polymer, Vol. 100 https://doi.org/10.1016/j.polymer.2016.06.062	journal	September 2016
Responsive hydrophobically associating polymers: a review of structure and properties Tonge, S. R.; Tighe, B. J. Advanced Drug Delivery Reviews, Vol. 53, Issue 1 https://doi.org/10.1016/s0169-409x(01)00223-x	journal	December 2001
Capturing Membrane Protein Ribosome Nascent Chain Complexes in a Native-like Environment for Co-translational Studies Pellowe, Grant A.; Findlay, Heather E.; Lee, Karen Biochemistry, Vol. 59, Issue 30 https://doi.org/10.1021/acs.biochem.0c00423	journal	July 2020
Solubilization and Stabilization of Membrane Proteins by Cycloalkane-Modified Amphiphilic Polymers Marconnet, Anaïs; Michon, Baptiste; Le Bon, Christel Biomacromolecules, Vol. 21, Issue 8 https://doi.org/10.1021/acs.biomac.0c00929	journal	June 2020
Influence of DIBMA Polymer Length on Lipid Nanodisc Formation and Membrane Protein Extraction Ball, Lauren E.; Riley, Liam J.; Hadasha, Waled Biomacromolecules, Vol. 22, Issue 2 https://doi.org/10.1021/acs.biomac.0c01538	journal	December 2020
Designing Mixed Detergent Micelles for Uniform Neutron Contrast Oliver, Ryan C.; Pingali, Sai Venkatesh; Urban, Volker S. The Journal of Physical Chemistry Letters, Vol. 8, Issue 20 https://doi.org/10.1021/acs.jpclett.7b02149	journal	October 2017
Small-Angle Neutron Scattering Reveals Energy Landscape for Rhodopsin Photoactivation Perera, Suchithranga M. D. C.; Chawla, Udeep; Shrestha, Utsab R. The Journal of Physical Chemistry Letters, Vol. 9, Issue 24 https://doi.org/10.1021/acs.jpclett.8b03048	journal	November 2018
Understanding the Structure and Dynamics of Complex Biomembrane Interactions by Neutron Scattering Techniques Qian, Shuo; Sharma, Veerendra Kumar; Clifton, Luke A. Langmuir, Vol. 36, Issue 50 https://doi.org/10.1021/acs.langmuir.0c02516	journal	December 2020
Contrast-Matched Isotropic Bicelles: A Versatile Tool to Specifically Probe the Solution Structure of Peripheral Membrane Proteins Using SANS Dos Santos Morais, Raphael; Delalande, Olivier; Pérez, Javier Langmuir, Vol. 33, Issue 26 https://doi.org/10.1021/acs.langmuir.7b01369	journal	June 2017
Formation of Lipid-Bilayer Nanodiscs by Diisobutylene/Maleic Acid (DIBMA) Copolymer Oluwole, Abraham Olusegun; Klingler, Johannes; Danielczak, Bartholomäus Langmuir, Vol. 33, Issue 50 https://doi.org/10.1021/acs.langmuir.7b03742	journal	December 2017
The Magic of Bicelles Lights Up Membrane Protein Structure Dürr, Ulrich H. N.; Gildenberg, Melissa; Ramamoorthy, Ayyalusamy Chemical Reviews, Vol. 112, Issue 11 https://doi.org/10.1021/cr300061w	journal	August 2012
Membrane Proteins Solubilized Intact in Lipid Containing Nanoparticles Bounded by Styrene Maleic Acid Copolymer Knowles, Timothy J.; Finka, Rachael; Smith, Corinne Journal of the American Chemical Society, Vol. 131, Issue 22 https://doi.org/10.1021/ja810046q	journal	June 2009
Bicelles Rich in both Sphingolipids and Cholesterol and Their Use in Studies of Membrane Proteins Hutchison, James M.; Shih, Kuo-Chih; Scheidt, Holger A. Journal of the American Chemical Society, Vol. 142, Issue 29 https://doi.org/10.1021/jacs.0c04669	journal	June 2020
Stable and Functional Rhomboid Proteases in Lipid Nanodiscs by Using Diisobutylene/Maleic Acid Copolymers Barniol-Xicota, Marta; Verhelst, Steven H. L. Journal of the American Chemical Society, Vol. 140, Issue 44 https://doi.org/10.1021/jacs.8b08441	journal	October 2018
Peptide-Induced Asymmetric Distribution of Charged Lipids in a Vesicle Bilayer Revealed by Small-Angle Neutron Scattering Qian, Shuo; Heller, William T. The Journal of Physical Chemistry B, Vol. 115, Issue 32 https://doi.org/10.1021/jp204045t	journal	August 2011
SANS from Poly(ethylene oxide)/Water Systems Hammouda, B.; Ho, D.; Kline, S. Macromolecules, Vol. 35, Issue 22 https://doi.org/10.1021/ma011657n	journal	October 2002
Insight into Clustering in Poly(ethylene oxide) Solutions Hammouda, Boualem; Ho, Derek L.; Kline, Steve Macromolecules, Vol. 37, Issue 18 https://doi.org/10.1021/ma049623d	journal	September 2004
Covalently circularized nanodiscs for studying membrane proteins and viral entry Nasr, Mahmoud L.; Baptista, Diego; Strauss, Mike Nature Methods, Vol. 14, Issue 1 https://doi.org/10.1038/nmeth.4079	journal	November 2016
Ab initio electron density determination directly from solution scattering data Grant, Thomas D. Nature Methods, Vol. 15, Issue 3 https://doi.org/10.1038/nmeth.4581	journal	January 2018
How many drug targets are there? Overington, John P.; Al-Lazikani, Bissan; Hopkins, Andrew L. Nature Reviews Drug Discovery, Vol. 5, Issue 12 https://doi.org/10.1038/nrd2199	journal	December 2006
Nanodiscs for structural and functional studies of membrane proteins Denisov, Ilia G.; Sligar, Stephen G. Nature Structural & Molecular Biology, Vol. 23, Issue 6 https://doi.org/10.1038/nsmb.3195	journal	June 2016
Influence of lipid bilayer properties on nanodisc formation mediated by styrene/maleic acid copolymers Cuevas Arenas, Rodrigo; Klingler, Johannes; Vargas, Carolyn Nanoscale, Vol. 8, Issue 32 https://doi.org/10.1039/c6nr02089e	journal	January 2016
An acid-compatible co-polymer for the solubilization of membranes and proteins into lipid bilayer-containing nanoparticles Hall, Stephen C. L.; Tognoloni, Cecilia; Charlton, Jack Nanoscale, Vol. 10, Issue 22 https://doi.org/10.1039/c8nr01322e	journal	January 2018
Homogeneous nanodiscs of native membranes formed by stilbene–maleic-acid copolymers Esmaili, Mansoore; Brown, Chanelle J.; Shaykhutdinov, Rustem Nanoscale, Vol. 12, Issue 32 https://doi.org/10.1039/d0nr03435e	journal	January 2020
Detergent-free purification of ABC (ATP-binding-cassette) transporters Gulati, Sonali; Jamshad, Mohammed; Knowles, Timothy J. Biochemical Journal, Vol. 461, Issue 2 https://doi.org/10.1042/bj20131477	journal	June 2014
Small-angle scattering by fractal systems Teixeira, J. Journal of Applied Crystallography, Vol. 21, Issue 6, p. 781-785 https://doi.org/10.1107/s0021889888000263	journal	December 1988
Small-angle neutron scattering and contrast variation: a powerful combination for studying biological structures Heller, William T. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 11 https://doi.org/10.1107/s0907444910017658	journal	October 2010
Stealth carriers for low-resolution structure determination of membrane proteins in solution Maric, Selma; Skar-Gislinge, Nicholas; Midtgaard, Søren Acta Crystallographica Section D Biological Crystallography, Vol. 70, Issue 2 https://doi.org/10.1107/s1399004713027466	journal	January 2014
ATSAS 2.8 : a comprehensive data analysis suite for small-angle scattering from macromolecular solutions Franke, D.; Petoukhov, M. V.; Konarev, P. V. Journal of Applied Crystallography, Vol. 50, Issue 4 https://doi.org/10.1107/s1600576717007786	journal	June 2017
BioXTAS RAW : improvements to a free open-source program for small-angle X-ray scattering data reduction and analysis Hopkins, Jesse Bennett; Gillilan, Richard E.; Skou, Soren Journal of Applied Crystallography, Vol. 50, Issue 5 https://doi.org/10.1107/s1600576717011438	journal	September 2017
Interpretation of solution scattering data from lipid nanodiscs Graziano, Vito; Miller, Lisa; Yang, Lin Journal of Applied Crystallography, Vol. 51, Issue 1 https://doi.org/10.1107/s1600576717018441	journal	February 2018
The suite of small-angle neutron scattering instruments at Oak Ridge National Laboratory Heller, William T.; Cuneo, Matthew; Debeer-Schmitt, Lisa Journal of Applied Crystallography, Vol. 51, Issue 2 https://doi.org/10.1107/s1600576718001231	journal	February 2018
Tissue-based map of the human proteome Uhlen, M.; Fagerberg, L.; Hallstrom, B. M. Science, Vol. 347, Issue 6220 https://doi.org/10.1126/science.1260419	journal	January 2015
An Algorithm for Least-Squares Estimation of Nonlinear Parameters Marquardt, Donald W. Journal of the Society for Industrial and Applied Mathematics, Vol. 11, Issue 2 https://doi.org/10.1137/0111030	journal	June 1963
New approach for membrane protein reconstitution into peptidiscs and basis for their adaptability to different proteins Angiulli, Gabriella; Dhupar, Harveer Singh; Suzuki, Hiroshi eLife, Vol. 9 https://doi.org/10.7554/elife.53530	journal	March 2020

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
DIBMA
Lipids
SANS
lipid nanodisc
lipid particle
membrane protein
membrane-mimetic
membranes
nanoparticles
neutron scattering
peptides and proteins
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small-angle scattering

Structure of Diisobutylene Maleic Acid Copolymer (DIBMA) and Its Lipid Particle as a “Stealth” Membrane-Mimetic for Membrane Protein Research

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