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  Inverse conformational selection in lipid–protein binding

Bacle, A., Buslaev, P., Garcia-Fandino, R., Favela-Rosales, F., Mendes Ferreira, T., Fuchs, P. F. J., et al. (2021). Inverse conformational selection in lipid–protein binding. Journal of the American Chemical Society, 143(34), 13701-13706. doi:10.1021/jacs.1c05549.

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Bacle, Amélie, Author
Buslaev, Pavel, Author
Garcia-Fandino, Rebeca, Author
Favela-Rosales, Fernando, Author
Mendes Ferreira, Tiago, Author
Fuchs, Patrick F. J., Author
Gushchin, Ivan, Author
Javanainen, Matti, Author
Kiirikki, Anne M., Author
Madsen, Jesper J., Author
Melcr, Josef, Author
Milán Rodríguez, Paula, Author
Miettinen, Markus S.1, Author           
Ollila, O. H. Samuli, Author
Papadopoulos, Chris G., Author
Peón, Antonio, Author
Piggot, Thomas J., Author
Piñeiro, Ángel, Author
Virtanen, Salla I., Author
Affiliations:
1Markus Miettinen, Theorie & Bio-Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_3070372              

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Free keywords: Lipids, Membranes, Protein structure, Conformation, Order
 Abstract: Interest in lipid interactions with proteins and other biomolecules is emerging not only in fundamental biochemistry but also in the field of nanobiotechnology where lipids are commonly used, for example, in carriers of mRNA vaccines. The outward-facing components of cellular membranes and lipid nanoparticles, the lipid headgroups, regulate membrane interactions with approaching substances, such as proteins, drugs, RNA, or viruses. Because lipid headgroup conformational ensembles have not been experimentally determined in physiologically relevant conditions, an essential question about their interactions with other biomolecules remains unanswered: Do headgroups exchange between a few rigid structures, or fluctuate freely across a practically continuous spectrum of conformations? Here, we combine solid-state NMR experiments and molecular dynamics simulations from the NMRlipids Project to resolve the conformational ensembles of headgroups of four key lipid types in various biologically relevant conditions. We find that lipid headgroups sample a wide range of overlapping conformations in both neutral and charged cellular membranes, and that differences in the headgroup chemistry manifest only in probability distributions of conformations. Furthermore, the analysis of 894 protein-bound lipid structures from the Protein Data Bank suggests that lipids can bind to proteins in a wide range of conformations, which are not limited by the headgroup chemistry. We propose that lipids can select a suitable headgroup conformation from the wide range available to them to fit the various binding sites in proteins. The proposed inverse conformational selection model will extend also to lipid binding to targets other than proteins, such as drugs, RNA, and viruses.

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Language(s): eng - English
 Dates: 2021-08-162021
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1021/jacs.1c05549
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Title: Journal of the American Chemical Society
  Other : JACS
  Abbreviation : J. Am. Chem. Soc.
Source Genre: Journal
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Publ. Info: Washington, DC : American Chemical Society
Pages: - Volume / Issue: 143 (34) Sequence Number: - Start / End Page: 13701 - 13706 Identifier: ISSN: 0002-7863