Thermodynamic Approach to Large-Scale Modeling of Alpha-Helices in Membranes

Abstract

A theoretical approach to large-scale modeling of α-helices in micelles and lipid bilayers has been developed. The FMAP (Folding of Membrane-Associated Peptides) method identifies potential α-helices in amino acid sequences of peptides and proteins, calculates their thermodynamic stability and membrane-binding affinity, and provides full-atomic 3D models arranged with respect to membranes. The method accounts for: (a) backbone enthalpic and entropic contributions and side chain secondary structure propensities, as described by a thermodynamic model of helix-coil transition (Framework1); (b) transfer free energy of α-helical and coil segments from water to anisotropic membrane environment (including the long-range electrostatics and first-shell solvation components), as described by implicit solvent model of the lipid bilayer (PPM2); and (c) van der Waals interactions and H-bonds between side chains, as defined by interatomic potentials derived from protein engineering data3,4. FMAP was thoroughly tested for more than a hundred of experimentally studied peptides. It was subsequently applied for modeling of transmembrane α-helical segments in ∼2500 single-spanning proteins from the entire human proteome. The results of the calculations are available in the Membranome database at membranome.org.1. Lomize AL, Mosberg HI. Thermodynamic model of secondary structure for alpha-helical peptides and proteins. Biopolymers 1997, 42:239-269.2. Lomize AL, Pogozheva ID, Mosberg HI. Anisotropic solvent model of the lipid bilayer. 2. Energetics of insertion of small molecules, peptides, and proteins in membranes. J Chem Inf Model 2011, 51:930-946.3. Lomize AL, Reibarkh MY, Pogozheva ID. Interatomic potentials and solvation parameters from protein engineering data for buried residues. Protein Sci 2002, 11:1984-2000.4. Lomize AL, Pogozheva ID, Mosberg HI. Quantification of helix-helix binding affinities in micelles and lipid bilayers. Protein Sci 2004, 13:2600-2612