Conformationally flexible core-bearing detergents with a hydrophobic or hydrophilic pendant: Effect of pendant polarity on detergent conformation and membrane protein stability
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Conformationally flexible core-bearing detergents with a hydrophobic or hydrophilic pendant : Effect of pendant polarity on detergent conformation and membrane protein stability. / Sadaf, Aiman; Kim, Seonghoon; Bae, Hyoung Eun; Wang, Haoqing; Nygaard, Andreas; Uegaki, Yuki; Du, Yang; Munk, Chastine F.; Katsube, Satoshi; Lee, Hyun Sung; Bae, Jungnam; Choi, Chul Won; Choi, Hee-Jung; Byrne, Bernadette; Gellman, Samuel H.; Guan, Lan; Loland, Claus J.; Kobilka, Brian K.; Im, Wonpil; Chae, Pil Seok.
In: Acta Biomaterialia, Vol. 128, 2021, p. 393-407.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Conformationally flexible core-bearing detergents with a hydrophobic or hydrophilic pendant
T2 - Effect of pendant polarity on detergent conformation and membrane protein stability
AU - Sadaf, Aiman
AU - Kim, Seonghoon
AU - Bae, Hyoung Eun
AU - Wang, Haoqing
AU - Nygaard, Andreas
AU - Uegaki, Yuki
AU - Du, Yang
AU - Munk, Chastine F.
AU - Katsube, Satoshi
AU - Lee, Hyun Sung
AU - Bae, Jungnam
AU - Choi, Chul Won
AU - Choi, Hee-Jung
AU - Byrne, Bernadette
AU - Gellman, Samuel H.
AU - Guan, Lan
AU - Loland, Claus J.
AU - Kobilka, Brian K.
AU - Im, Wonpil
AU - Chae, Pil Seok
PY - 2021
Y1 - 2021
N2 - Membrane protein structures provide atomic level insight into essential biochemical processes and facilitate protein structure-based drug design. However, the inherent instability of these bio-macromolecules outside lipid bilayers hampers their structural and functional study. Detergent micelles can be used to solubilize and stabilize these membrane-inserted proteins in aqueous solution, thereby enabling their downstream characterizations. Membrane proteins encapsulated in detergent micelles tend to denature and aggregate over time, highlighting the need for development of new amphiphiles effective for protein solubility and stability. In this work, we present newly-designed maltoside detergents containing a pendant chain attached to a glycerol-decorated tris(hydroxymethyl)methane (THM) core, designated GTMs. One set of the GTMs has a hydrophobic pendant (ethyl chain; E-GTMs), and the other set has a hydrophilic pendant (methoxyethoxylmethyl chain; M-GTMs) placed in the hydrophobic-hydrophilic interfaces. The two sets of GTMs displayed profoundly different behaviors in terms of detergent self-assembly and protein stabilization efficacy. These behaviors mainly arise from the polarity difference between two pendants (ethyl and methoxyethoxylmethyl chains) that results in a large variation in detergent conformation between these sets of GTMs in aqueous media. The resulting high hydrophobic density in the detergent micelle interior is likely responsible for enhanced efficacy of the M-GTMs for protein stabilization compared to the E-GTMs and a gold standard detergent DDM. A representative GTM, M-GTM-O12, was more effective for protein stability than some recently developed detergents including LMNG. This is the first case study investigating the effect of pendant polarity on detergent geometry correlated with detergent efficacy for protein stabilization. Statement of significance This study introduces new amphiphiles for use as biochemical tools in membrane protein studies. We identified a few hydrophilic pendant-bearing amphiphiles such as M-GTM-O11 and M-GTM-O12 that & nbsp;show remarkable efficacy for membrane protein solubilization and stabilization compared to a gold stan-dard DDM, the hydrophobic counterparts (E-GTMs) and a significantly optimized detergent LMNG. In ad-dition, detergent results obtained in the current study reveals the effect of detergent pendant polarity on protein solubility and stability. Thus, the current study represents both significant chemical and con-ceptual advance. The detergent tools and design principle introduced here advance protein science and facilitate structure-based drug design and development. (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
AB - Membrane protein structures provide atomic level insight into essential biochemical processes and facilitate protein structure-based drug design. However, the inherent instability of these bio-macromolecules outside lipid bilayers hampers their structural and functional study. Detergent micelles can be used to solubilize and stabilize these membrane-inserted proteins in aqueous solution, thereby enabling their downstream characterizations. Membrane proteins encapsulated in detergent micelles tend to denature and aggregate over time, highlighting the need for development of new amphiphiles effective for protein solubility and stability. In this work, we present newly-designed maltoside detergents containing a pendant chain attached to a glycerol-decorated tris(hydroxymethyl)methane (THM) core, designated GTMs. One set of the GTMs has a hydrophobic pendant (ethyl chain; E-GTMs), and the other set has a hydrophilic pendant (methoxyethoxylmethyl chain; M-GTMs) placed in the hydrophobic-hydrophilic interfaces. The two sets of GTMs displayed profoundly different behaviors in terms of detergent self-assembly and protein stabilization efficacy. These behaviors mainly arise from the polarity difference between two pendants (ethyl and methoxyethoxylmethyl chains) that results in a large variation in detergent conformation between these sets of GTMs in aqueous media. The resulting high hydrophobic density in the detergent micelle interior is likely responsible for enhanced efficacy of the M-GTMs for protein stabilization compared to the E-GTMs and a gold standard detergent DDM. A representative GTM, M-GTM-O12, was more effective for protein stability than some recently developed detergents including LMNG. This is the first case study investigating the effect of pendant polarity on detergent geometry correlated with detergent efficacy for protein stabilization. Statement of significance This study introduces new amphiphiles for use as biochemical tools in membrane protein studies. We identified a few hydrophilic pendant-bearing amphiphiles such as M-GTM-O11 and M-GTM-O12 that & nbsp;show remarkable efficacy for membrane protein solubilization and stabilization compared to a gold stan-dard DDM, the hydrophobic counterparts (E-GTMs) and a significantly optimized detergent LMNG. In ad-dition, detergent results obtained in the current study reveals the effect of detergent pendant polarity on protein solubility and stability. Thus, the current study represents both significant chemical and con-ceptual advance. The detergent tools and design principle introduced here advance protein science and facilitate structure-based drug design and development. (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
KW - Pendant polarity
KW - Detergent conformation
KW - Membrane proteins
KW - Protein stabilization
KW - Amphiphile design
KW - RESONANCE ENERGY-TRANSFER
KW - ESCHERICHIA-COLI
KW - MELIBIOSE PERMEASE
KW - GNG AMPHIPHILES
KW - RECEPTOR
KW - BINDING
KW - GUI
KW - CRYSTALLIZATION
KW - SOLUBILIZATION
KW - STABILIZATION
U2 - 10.1016/j.actbio.2021.04.043
DO - 10.1016/j.actbio.2021.04.043
M3 - Journal article
C2 - 33933694
VL - 128
SP - 393
EP - 407
JO - Acta Biomaterialia
JF - Acta Biomaterialia
SN - 1742-7061
ER -
ID: 273531081