Inverse Conformational Selection in Lipid-Protein Binding.

Area of Science:

• Biochemistry and Nanobiotechnology
• Molecular Biophysics

Background:

• Lipid headgroups on membranes and nanoparticles mediate interactions with biomolecules.
• Understanding lipid headgroup conformations is crucial for fields like nanobiotechnology (e.g., mRNA vaccine carriers).
• Previous studies lacked experimental data on lipid headgroup conformational ensembles under physiological conditions.

Purpose of the Study:

• To determine the conformational ensembles of key lipid headgroups in biologically relevant conditions.
• To investigate whether lipid headgroups adopt a few rigid structures or a continuous spectrum of conformations.
• To explore the implications of lipid headgroup flexibility for biomolecular interactions.

Main Methods:

• Combined solid-state Nuclear Magnetic Resonance (NMR) experiments and molecular dynamics (MD) simulations (NMRlipids Project).
• Analyzed four key lipid types under various conditions.
• Examined 894 protein-bound lipid structures from the Protein Data Bank (PDB).

Main Results:

• Lipid headgroups sample a broad, overlapping range of conformations in neutral and charged membranes.
• Headgroup chemistry influences the probability distribution of conformations, not the range itself.
• Lipids bind to proteins in diverse conformations, irrespective of headgroup chemistry.

Conclusions:

• Lipid headgroups possess extensive conformational flexibility.
• Lipids utilize this flexibility to select appropriate conformations for binding to diverse protein sites.
• The proposed inverse conformational selection model applies to lipid interactions with proteins, drugs, RNA, and viruses.