Large-Scale Computational Analysis of Protein Arrangement in the Lipid Bilayer

Abstract

Spatial arrangements in the lipid bilayer of more than 1500 integral and peripheral membrane proteins with known 3D structures were calculated using a new continuum anisotopic solvent model of the lipid bilayer. The new model accounts for hydrophobic, hydrogen bonding, and long-range electrostatic solute-solvent interactions and includes the preferential solvation of protein groups by water. The model implements empirical dependencies of atomic solvation parameters and electrostatic energy terms on the bulk solvent properties including its dielectric constant (ε), hydrogen bonding acidity and basicity (α, β) and dipolarity/polarizability parameter (π∗). The dependencies were determined from 1269 partition coefficients of neutral molecules and ions from water to 19 solvents. The transmembrane profiles of polarity parameters (ε, α, β, π∗) in DOPC and DOPS bilayers were calculated based on published distributions of lipid fragments and water along the bilayer normal obtained in X-ray diffraction, neutron scattering and ESR studies. The obtained profiles indicate the existence of a “mid-polar” region (9 to 16 Å from the membrane center) that provides a significant energy gain from the hydrophobic interactions of nonpolar groups, but only a small electrostatic energy penalty associated with transfer of polar hydrogen-bonding groups and dipoles from water to this region. This explains the preferential accumulation of protein “hydrophobic dipoles” (aromatic rings of Trp and Tyr residues) in the “mid-polar” region. The results of the calculations have been included in the second version of the OPM database at opm.phar.umich.edu. The developed method and the database were applied for identification and functional assignment of potential membrane-associated proteins, planning mutagenesis experiments to verify the predicted membrane binding mode of peripheral proteins, prediction and interpretation of experimental membrane binding data.