A Systematic Analysis of Lipid-Protein Interactions in the Protein Data Bank

Lipid-protein interactions are ubiquitous in biology, where they are fundamental to membrane structure, cell signaling, immunology, and metabolism. Despite the availability of thousands of experimentally determined lipid-protein structures, the molecular basis for lipid recognition and specificity across the lipid-protein interactome remains incompletely understood. Here, we report a systematic analysis of 113,782 annular and nonannular lipid-protein complexes spanning the eight lipid classes. Pairwise atomic interactions are linked to lipid and protein physicochemical properties and binding geometries. Hydrophobic contacts, hydrogen bonds, and salt bridges contributed to over 99% of lipid-protein interactions. Lipid class-, protein sublocalization-, protein function-, and protein fold-dependent trends were identified. Protein pockets were finely tuned for lipid size, shape, and polarity: fatty acyls associated with narrow, moderately hydrophobic pockets; saccharolipids and glycerophospholipids bound to larger, polar cavities; and sterols and prenols preferentially occupied compact hydrophobic sites. Global analysis across different protein families identified similarities in interaction profiles, while also highlighting protein-specific recognition adapted to biochemical function. Lipid-protein interaction maps were projected onto lipid structures to uncover conserved and divergent hotspots and coldspots across lipid classes. The heatmaps imply that recognition and specificity are mediated by tailored anchoring of polar head groups and varying interaction with hydrophobic tails. Together, the data establish nature's principles governing lipid binding, lipid selectivity, and complex stability, and collectively provide a molecular atlas of the lipid-protein interactome. The work enables the elucidation of lipid biology at scale and establishes guiding principles for the rational design of chemical probes and therapeutics targeting lipid biology.