Free Energy Landscape of Lipid Interactions with Regulatory Binding Sites on the Transmembrane Domain of the EGF Receptor.
Lipid molecules can bind to specific sites on integral membrane proteins, modulating their structure and function. We have undertaken coarse-grained simulations to calculate free energy profiles for glycolipids and phospholipids interacting with modulatory sites on the transmembrane helix dimer of the EGF receptor within a lipid bilayer environment. We identify lipid interaction sites at each end of the transmembrane domain and compute interaction free energy profiles for lipids with these sites. Interaction free energies ranged from ca. -40 to -4 kJ/mol for different lipid species. Those lipids (glycolipid GM3 and phosphoinositide PIP2) known to modulate EGFR function exhibit the strongest binding to interaction sites on the EGFR, and we are able to reproduce the preference for interaction with GM3 over other glycolipids suggested by experiment. Mutation of amino acid residues essential for EGFR function reduce the binding free energy of these key lipid species. The residues interacting with the lipids in the simulations are in agreement with those suggested by experimental (mutational) studies. This approach provides a generalizable tool for characterizing the interactions of lipids that bind to specific sites on integral membrane proteins.
Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, United Kingdom.
George
G
Hedger
Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, United Kingdom.|MRC Cancer Unit, University of Cambridge , MRC Research Centre, Box 197, Cambridge CB2 0X1, United Kingdom.
David
D
Shorthouse
Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, United Kingdom.|D. E. Shaw Research , 120 West 45th Street, 39th floor, New York, New York 10036, United States.
Heidi
H
Koldsø
Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, United Kingdom.
Mark S P
MS
Sansom
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism; D005679:G(M3) Ganglioside / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D013816:Thermodynamics
D005679:G(M3) Ganglioside; D008051:Lipid Bilayers; D019269:Phosphatidylinositol 4,5-Diphosphate; C512478:EGFR protein, human; D066246:ErbB Receptors