Lipid recognition propensities of amino acids in membrane proteins from atomic resolution data

To gain an insight into the molecular mechanisms of the recognition of lipid molecules by membrane proteins, we investigated amino acid propensities in membrane proteins for interacting with the head and tail groups of lipid molecules. We observed a common pattern of lipid tail-amino acid interactions in two different data sources, crystal structures and molecular dynamics simulations. These interactions are largely explained by general lipophilicity, whereas the preferences for lipid head groups vary among individual proteins. We also found that membrane and water-soluble proteins utilize essentially an identical set of amino acids for interacting with lipid head and tail groups.We showed that the lipophilicity of amino acid residues determines the amino acid preferences for lipid tail groups in both membrane and water-soluble proteins, suggesting that tightly-bound lipid molecules and lipids in the annular shell interact with membrane proteins in a similar manner. In contrast, interactions between lipid head groups and amino acids showed a more variable pattern, apparently constrained by each protein's specific molecular function.About 20-30% of all proteins encoded in a typical genome are estimated to be localized in membranes [1,2], where protein-lipid interactions play crucial roles in the conformational stability and biological functions of membrane proteins. Many experimental studies have suggested that physico-chemical properties of the membrane lipid bilayer influence the stability and function of membrane proteins. The thermal [3,4] and chemical [5] stability of the potassium channel KcsA has been shown to vary according to the lipid composition of the membrane bilayer. It has also been shown that the lipid composition affects protein functions including: ion transport in KcsA [6,7] and the Ca2+-ATPase of sarcoplasmic reticulum [8,9], phosphorylation by the diacylglycerol kinase [10] and chemical compound transport by the mechanosensitive channel of large