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Published January 26, 2021 | Supplemental Material
Journal Article Open

Properties of DNA- and Protein-Scaffolded Lipid Nanodiscs

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.

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.

Attached Files

Supplemental Material - nn0c07128_si_001.pdf

Supplemental Material - nn0c07128_si_002.mpg

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Supplemental Material - nn0c07128_si_008.mpg

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