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Properties of DNA- and Protein-Scaffolded Lipid Nanodiscs

Maingi, Vishal and Rothemund, Paul W. K. (2021) Properties of DNA- and Protein-Scaffolded Lipid Nanodiscs. ACS Nano, 15 (1). pp. 751-764. ISSN 1936-0851. https://resolver.caltech.edu/CaltechAUTHORS:20201224-122234932

[img] PDF (DNA, protein, and hybrid DNA–protein scaffold model building; description of membrane thickness and order parameter analyses; SMD simulation details; additional supporting figures) - Supplemental Material
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[img] Video (MPEG) (Movie S1: Last 20 ns of simulation for circNW11 from Figure 2A) - Supplemental Material
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[img] Video (MPEG) (Movie S2: Last 20 ns of simulation for dec_select-DNA11 from Figure 2B) - Supplemental Material
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[img] Video (MPEG) (Movie S3: Last 20 ns of simulation for et_all-DNA11 from Figure 2C) - Supplemental Material
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[img] Video (MPEG) (Movie S4: Last 20 ns of simulation for dec_select-DNA15 from Figure 4A) - Supplemental Material
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[img] Video (MPEG) (Movie S5: Last 20 ns of simulation for et_all-DNA15 from Figure 4B) - Supplemental Material
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[img] Video (MPEG) (Movie S6: Last 10 ns of simulation for et_all-hexDNA45 from Figure 6A) - Supplemental Material
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[img] Video (MPEG) (Movie S7: Last 10 ns of simulation for hexDNA::NW11 from Figure 6B) - Supplemental Material
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Abstract

The properties of natural lipid bilayers are vital to the regulation of many membrane proteins. Scaffolded nanodiscs provide an in vitro lipid bilayer platform to host membrane proteins in an environment that approximates native lipid bilayers. However, the properties of scaffold-enclosed bilayers may depart significantly from those of bulk cellular membranes. Therefore, to improve the usefulness of nanodiscs it is essential to understand the properties of lipids restricted by scaffolds. We used computational molecular dynamics and modeling approaches to understand the effects of nanodisc size, scaffold type (DNA or protein), and hydrophobic modification of DNA scaffolds on bilayer stability and degree to which the properties of enclosed bilayers approximate bulk bilayers. With respect to achieving bulk bilayer behavior, we found that charge neutralization of DNA scaffolds was more important than the total hydrophobic content of their modifications: bilayer properties were better for scaffolds having a large number of short alkyl chains than those having fewer long alkyl chains. Further, complete charge neutralization of DNA scaffolds enabled better lipid binding, and more stable bilayers, as shown by steered molecular dynamics simulations that measured the force required to dislodge scaffolds from lipid bilayer patches. Considered together, our simulations provide a guide to the design of DNA-scaffolded nanodiscs suitable for studying membrane proteins.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acsnano.0c07128DOIArticle
ORCID:
AuthorORCID
Maingi, Vishal0000-0003-3861-7973
Rothemund, Paul W. K.0000-0002-1653-3202
Additional Information:© 2020 American Chemical Society. Received: August 24, 2020; Accepted: December 1, 2020; Published: December 21, 2020. V.M. thanks Mark S. P. Sansom for initial talks concerning small-sized nanodiscs, which seeded the motivation for this study, and Helgi Ingólfsson for MARTINI force field discussions. V.M. acknowledges a Human Frontier Science Program Postdoctoral fellowship and cloud computation credits from Amazon Web Services-Caltech program. P.W.K.R. acknowledges the National Science Foundation (1636364) and the Office of Naval Research (N00014-18-12649 and N00014-17-12610). Author Contributions. V.M. designed the computational studies, and performed and analysed all simulations. V.M. and P.W.K.R. discussed and wrote the manuscript. The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
Human Frontier Science ProgramUNSPECIFIED
Amazon Web ServicesUNSPECIFIED
NSFCMMI-1636364
Office of Naval Research (ONR)N00014-17-12610
Subject Keywords:nanodiscs, lipid−DNA interaction, lipid−protein interaction, membrane scaffolds, computational design, molecular dynamics, DNA origami
Issue or Number:1
Record Number:CaltechAUTHORS:20201224-122234932
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20201224-122234932
Official Citation:Properties of DNA- and Protein-Scaffolded Lipid Nanodiscs. Vishal Maingi and Paul W. K. Rothemund. ACS Nano 2021 15 (1), 751-764; DOI: 10.1021/acsnano.0c07128
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:107286
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:04 Jan 2021 17:10
Last Modified:28 Jan 2021 22:01

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