Membrane contact probability: An essential and predictive character for the structural and functional studies of membrane proteins

One of the unique traits of membrane proteins is that a significant fraction of their hydrophobic amino acids is exposed to the hydrophobic core of lipid bilayers rather than being embedded in the protein interior, which is often not explicitly considered in the protein structure and function predictions. Here, we propose a characteristic and predictive quantity, the membrane contact probability (MCP), to describe the likelihood of the amino acids of a given sequence being in direct contact with the acyl chains of lipid molecules. We show that MCP is complementary to solvent accessibility in characterizing the outer surface of membrane proteins, and it can be predicted for any given sequence with a machine learning-based method by utilizing a training dataset extracted from MemProtMD, a database generated from molecular dynamics simulations for the membrane proteins with a known structure. As the first of many potential applications, we demonstrate that MCP can be used to systematically improve the prediction precision of the protein contact maps and structures.Author summary: The distribution of residues on protein surfaces is largely determined by the surrounding environment. For soluble proteins, most of the residues on the outer surface are hydrophilic, and people use the quantity “solvent accessibility” to describe and predict these surface residues. In contrast, for membrane proteins that are embedded in a lipid bilayer, many of their surface residues are hydrophobic and membrane-contacting, but there is yet a widely-accepted quantity for the description or prediction of this characteristic property. Here, we propose a new quantity termed “membrane contact probability (MCP)”, which can be used to describe and predict the membrane-contacting surface residues of proteins. We also propose a machine learning-based method to predict MCP from protein sequences, utilizing the dataset generated by physics-based computer simulations. We demonstrate that a quantity such as MCP is helpful for protein structure prediction, and we believe that it will find broad applications in the structure and function studies of membrane proteins.