Here we present a combined method to study mutual effects of a protein and a membrane upon the dimerization of transmembrane (TM) α-helical peptides. The approach is based on the numerical decomposition of dimerization free energy profiles for TM helices into components corresponding to different interaction types and on the mapping of the distribution of the average lipid density around the protein. The method was tested on the TM domains of human glycophorin A (GpA) and several model peptides. It is shown that lipids contribute significantly to a total free energy of dimerization, and the direct protein-protein contacts may be unfavorable. Also, we found some lipid acyl chains binding sides on the surface of TM domains of GpA. Thus, the amino acid sequence determines not only the protein- protein contacts during dimerization, but also the interactions with lipids, and that can determine the detailed balance between the free energy contributions. Lipid membrane can act as an active driving force in the process of TM helices association. The look rather promising for further rational design of peptide modulators aimed to interact with bitopic membrane proteins, including receptor tyrosine kinases.
transmembrane domains, dimerization energy, membrane proteins, glycophorin A
1. Bagatolli L.A., Ipsen J.H., Simonsen A.C., Mouritsen O.G. An outlook on organization of lipids in membranes: Searching for a realistic connection with the organization of biological membranes. Prog. Lipid Res., 2010, vol. 49, no. 4, pp. 378-389.
2. Teese M.G., Langosch D. Role of GxxxG Motifs in Transmembrane Domain Interactions. Biochemistry, 2015, vol. 54, no. 33, pp. 5125-5135.
3. Regad T. Targeting RTK Signaling Pathways in Cancer. Cancers, 2015, vol. 7, no. 3, pp. 1758-1784.
4. Arpel A., Sawma P. [et al.] Transmembrane domain targeting peptide antagonizing ErbB2/Neu inhibits breast tumor growth and metastasis. Cell Rep., 2014, vol. 8, no. 6, pp. 1714-1721.
5. Li E., Hristova K. Receptor tyrosine kinase transmembrane domains: Function, dimer structure and dimerization energetics. Cell Adhes. Migr., 2010, vol. 4, no. 2, pp. 249-254.
6. Sawma P., Roth L. [et al.] Evidence for New Homotypic and Heterotypic Interactions between Transmembrane Helices of Proteins Involved in Receptor Tyrosine Kinase and Neuropilin Signaling. J. Mol. Biol., 2014, vol. 426, no. 24, pp. 4099-4111.
7. Fink A., Sal-Man N., Gerber D., Shai Y. Transmembrane domains interactions within the membrane milieu: Principles, advances and challenges. Biochim. Biophys. Acta - Biomembr., 2012, vol. 1818, no. 4, pp. 974-983.
8. Anbazhagan V., Schneider D. The membrane environment modulates self-association of the human GpA TM domain - Implications for membrane protein folding and transmembrane signaling. Biochim. Biophys. Acta - Biomembr., 2010, vol. 1798, no. 10, pp. 1899-1907.
9. Bocharov E.V., Mayzel M.L. [et al.] Spatial Structure and pH-dependent Conformational Diversity of Dimeric Transmembrane Domain of the Receptor Tyrosine Kinase EphA1. J. Biol. Chem., 2008, vol. 283, no. 43, pp. 29385-29395.
10. Caputo G.A. Analyzing the Effects of Hydrophobic Mismatch on Transmembrane α-Helices Using Tryptophan Fluorescence Spectroscopy. in Membrane Proteins, ed. by G. Ghirlanda and A. Senes, Humana Press, 2013, pp. 95-116.
11. Van Der Spoel D., Lindahl E., Hess B., Groenhof G., Mark A.E., Berendsen H.J.C. GROMACS: Fast, flexible, and free. J. Comput. Chem., 2005, vol. 26, no. 16, pp. 1701-1718.
12. Berger O., Edholm O., Jähnig F. Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature. Biophys. J., 1997, vol. 72, no. 5, pp. 2002-2013.
13. Mineev K.S., Bocharov E.V. [i dr.] Struktura dimera transmembrannogo domena glikoforina A v okruzhenii lipidov i detergentov. Acta Naturae, 2011, t. 3, № 2, s. 94-102. [Mineev K.S., Bocharov E.V. [et al.] Dimeric structure of the transmembrane domain of glycophorin a in lipidic and detergent environments. Acta Naturae, 2011, vol. 3, no. 2, pp. 90-98. (In Russ.)]
14. Kuznetsov A.S., Polyansky A.A., Fleck M., Volynsky P.E., Efremov R.G. Adaptable Lipid Matrix Promotes Protein-Protein Association in Membranes. J. Chem. Theory Comput., 2015, vol. 11, no. 9, pp. 4415-4426. [Kuznetsov A.S., Polyansky A.A., Fleck M., Volynsky P.E., Efremov R.G., Adaptable Lipid Matrix Promotes Protein- Protein Association in Membranes. J. Chem. Theory Comput., 2015, vol. 11, no. 9, pp. 4415-4426. (In Russ.)]
15. Kuznecov A.S., Volynskiy P.E., Efremov R.G. Rol' lipidnogo okruzheniya v processe dimerizacii transmembrannyh domenov glikoforina A. Acta Naturae, 2015, t. 7, № 4, s. 135-140. [Kuznetsov A.S., Volynsky P.E., Efremov R.G., Role of the Lipid Environment in the Dimerization of Transmembrane Domains of Glycophorin A. Acta Naturae, 2015, vol. 7, no. 4, pp. 122-127. (In Russ.)]
