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.

CEA CNRS Institute for Integrative Biology of the Cell Université Paris Saclay Gif sur Yvette 91198 France

Center for Research in Biological Chemistry and Molecular Materials Universidade de Santiago de Compostela Santiago de Compostela E 15782 Spain

Chemistry University of Southampton Highfield Southampton SO17 1BJ United Kingdom

CIQUP Centro de Investigao em Química Departamento de Química e Bioquímica Faculdade de Ciências Universidade do Porto Porto 4169 007 Portugal

Departamento de Ciencias Básicas Tecnológico Nacional de México ITS Zacatecas Occidente Sombrerete Zacatecas 99102 México

Departamento de Física Aplicada Facultade de Física Universidade de Santiago de Compostela Santiago de Compostela E 15782 Spain

Department of Chemistry The University of Chicago Chicago Illinois 60637 United States

Department of Theory and Bio Systems Max Planck Institute of Colloids and Interfaces Potsdam 14424 Germany

Ecole Normale Supérieure PSL University CNRS Laboratoire des Biomolécules Sorbonne Université Paris 75005 France

Global and Planetary Health College of Public Health University of South Florida Tampa Florida 33612 United States

Groningen Biomolecular Sciences and Biotechnology Institute and The Zernike Institute for Advanced Materials University of Groningen Groningen9747 AG The Netherlands

Institute of Biotechnology University of Helsinki Helsinki 00014 Finland

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 542 2 Prague CZ 16610 Czech Republic

Laboratoire Coopératif Lipotoxicity and Channelopathies ConicMeds Université de Poitiers 1 rue Georges Bonnet Poitiers 86000 France

Nanoscience Center and Department of Chemistry University of Jyväskylä P O Box 35 Jyväskylä 40014 Finland

NMR group Institute for Physics Martin Luther University Halle Wittenberg Halle 06120 Germany

Research Center for Molecular Mechanisms of Aging and Age related Diseases Moscow Institute of Physics and Technology Dolgoprudny 141701 Russia

UFR Sciences du Vivant Université de Paris Paris 75013 France

Citace poskytuje Crossref.org

Effective Inclusion of Electronic Polarization Improves the Description of Electrostatic Interactions: The prosECCo75 Biomolecular Force Field

Overlay databank unlocks data-driven analyses of biomolecules for all

Quantitative Comparison against Experiments Reveals Imperfections in Force Fields' Descriptions of POPC-Cholesterol Interactions