Design Principles of Membrane Protein Structures

Abstract

Membrane proteins play key role in cellular signaling and ion transport. Statistical analysis of expanding database of high-resolution membrane protein structures in Protein Data Bank (PDB) provides useful information about membrane protein structure and function. We used RosettaMembrane software (Yarov-Yarovoy V et al (2006) Proteins) to analyze ∼300 unique alpha helical membrane protein structures in PDB and derive knowledge based energy function for membrane protein structure prediction, membrane protein-protein docking, and membrane protein design. The RosettaMembrane residue environment energy term is based on amino acid propensities in hydrophobic, interface, and water layers of the membrane and depends on the residue burial state - from being completely buried within a protein environment to being completely exposed either to the lipid or water environments. Residue buried state is determined from the number of residue neighbors within 6 and 10 A spheres. The RosettaMembrane residue-residue interaction term is based on the propensities of amino acid pairs to be in close proximity to each other within hydrophobic, interface, and water layers. Results of our statistical analysis reveal fine details of favorable and unfavorable environments for all amino acids types in all membrane layers and residue burial states. We find that large hydrophobic amino acids are favorable facing the hydrophobic core of the lipid bilayer. Small amino acids are favorable facing the protein core within the hydrophobic layer of the membrane. Aromatic or positively charged amino acids and favorable facing the lipid head groups. Residue-residue interactions are often favored between polar and charged amino acids and also between some of small and large hydrophobic amino acids inside of the protein core within the hydrophobic layer of the membrane. These data will be useful for rational design of novel membrane protein structures and functions.