Adaptable Lipid Matrix Promotes Protein–Protein Association in Membranes

Abstract

The cell membrane is "stuffed" with proteins, whose transmembrane (TM) helical domains spontaneously associate to form functionally active complexes. For a number of membrane receptors, a modulation of TM domains' oligomerization has been shown to contribute to the development of severe pathological states, thus calling for detailed studies of the atomistic aspects of the process. Despite considerable progress achieved so far, several crucial questions still remain: How do the helices recognize each other in the membrane? What is the driving force of their association? Here, we assess the dimerization free energy of TM helices along with a careful consideration of the interplay between the structure and dynamics of protein and lipids using atomistic molecular dynamics simulations in the hydrated lipid bilayer for three different model systems - TM fragments of glycophorin A, polyalanine and polyleucine peptides. We observe that the membrane driven association of TM helices exhibits a prominent entropic character, which depends on the peptide sequence. Thus, a single TM peptide of a given composition induces strong and characteristic perturbations in the hydrophobic core of the bilayer, which may facilitate the initial "communication" between TM helices even at the distances of 20-30 Å. Upon tight helix-helix association, the immobilized lipids accommodate near the peripheral surfaces of the dimer, thus disturbing the packing of the surrounding. The dimerization free energy of the modeled peptides corresponds to the strength of their interactions with lipids inside the membrane being the lowest for glycophorin A and similarly higher for both homopolymers. We propose that the ability to accommodate lipid tails determines the dimerization strength of TM peptides and that the lipid matrix directly governs their association.

Conformational Changes in the Epidermal Growth Factor Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained MetaDynamics Free Energy Calculations

“…Similar behavior was observed regarding the rotational motions, even leading in some case to the absence of interconversion in the course of simulations (Figure 7B). These findings support the view that the bilayer thickness can modulate TM helix dimer stability, 37,38,76 and that the physical properties of plasma membrane (nano)domains may be able to modulate receptor activation. 2,84,85 Indeed, in future studies it would be of interest to explore the dependence of free energy landscape on more complex lipid bilayer compositions, including interactions with, e.g., cholesterol and phosphatidylinositol 4,5-bisphosphate such as have been observed in, e.g., simulations with GPCRs.…”

Convergence and Sampling in Determining Free Energy Landscapes for Membrane Protein Association

“…For the native state the well-depth observed is −28 kJ/mol, which compares well with other PMF-based estimates of −30 kJ/mol 67 and −40 kJ/mol 4 from CG simulations, and of −44 kJ/mol 45 and −60 kJ/mol 68 from all-atom simulations. However, while the CG force field can qualitatively reproduce the effect of a dimer-disrupting mutation on the native bound conformation, it does not appreciably alter the dimer stability.…”

Lipid-Loving ANTs: Molecular Simulations of Cardiolipin Interactions and the Organization of the Adenine Nucleotide Translocase in Model Mitochondrial Membranes

“…72 However, within a membrane environment, the model performs well, with the free energy profiles for glycophorin A transmembrane helix dimerization estimated to be approximately −30 to −40 kJ/mol in MARTINI CG, 73,74 and −45 to −60 kJ/mol in all-atom simulations, 75,76 which agree reasonably with available experimental data. 77 The application of MARTINI dihedral restraints together with an ElNeDyn elastic network 31 prohibits conformational transitions, and thus, we consider only the cytoplasm-facing state of the translocase, for which crystal structures are known.…”