Lipid-protein interactions in cells are involved in various biological processes, including metabolism, trafficking, signaling, host-pathogen interactions, and transmembrane transport (Sych et al. 2022; PMID 34982570). At the plasma membrane, lipid-protein interactions play major roles in membrane organization and function. Several membrane proteins have motifs for specific lipid binding, which modulate protein conformation and consequent function. In addition to such specific lipid-protein interactions, protein function can be regulated by the dynamic, collective behavior of lipids in membranes. Emerging analytical, biochemical, and computational technologies allow the study of the influence of specific lipid-protein interactions, as well as the collective behavior of membranes on protein function (Sych et al. 2022; PMID 34982570).

Inner membrane proteins (IMPs) are solvated by a compositionally and biophysically complex lipid matrix. These solvating lipids affect protein structure and function in a variety of ways, from stereospecific, high-affinity protein-lipid interactions to modulation by bulk membrane properties (Levental and Lyman 2022). Specific examples of functional modulation of IMPs by their solvating membranes have been reported for various transporters, channels and signal receptors; however, generalizable mechanistic principles governing IMP regulation by lipid environments are neither widely appreciated nor completely understood. Levental and Lyman 2022 reviewed insights into the inter-relationships between complex lipidomes of mammalian membranes, the membrane physicochemical properties resulting from such lipid collectives, and the regulation of IMPs by either or both. The recent proliferation of high-resolution methods to study such lipid-protein interactions has led to generalizable insights, which allow synthesis into a general framework termed the 'functional paralipidome' to understand the mutual regulation between membrane proteins and their surrounding lipid microenvironments.