Молекулярное моделирование биомембран и их комплексов с трансмембранными α-спиралями белков
Natural polycationic membrane-active peptides typically lack disulfide bonds and exhibit fusion, cell-penetrating, antimicrobial activities. They are mostly unordered in solution, but adopt a helical structure, when bound to phospholipid membranes. Structurally different are cardiotoxins (or cytotoxins, СTs) from cobra venom. They are fully b-structured molecules, characterized by the three-finger fold (TFF). Affinity of CTs to lipid bilayer was shown to depend on amino acid sequence in the tips of the three loops. In the present review, CT-membrane interactions are analyzed through the prism of data on binding of the toxins to phospholipid liposomes and detergent micelles, as well as their structural and computational studies in membrane mimicking environments. We assess different hydrophobicity scales to compare membrane partitioning of various CTs and their membrane effects. A comparison of hydrophobic/hydrophilic properties of CTs and linear polycationic peptides provides a key to their biological activity and reveal rationality for design of new membrane-interacting compounds. Finally, since the viewpoint of the data obtained on model lipid membranes, cytotoxic activity of CTs against cancer cells is discussed.
Basing on the information about the structure of the solution and asymptotic estimates in the problem of steady flow across the root, a system of algebraic relations similar to the commonly used compartment models is obtained. As compared with these, the method proposed has an important advantage making it possible to take into account the characteristic features of the anatomical structure of the root and the non-uniformity of the parameter distribution over its cross-section. This enables us to formulate simple finite relationships fitting with sufficient accuracy with the numerical solution obtained within the framework of the continuum model. The application of the approach proposed to solving specific problems is simpler than both the numerical solution based on the continuum model and the solution obtained by asymptotic methods.
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. © 2015 American Chemical Society.
A computational approach to the analysis of structural and dynamical properties of all components of model membranes - membrane proteins, lipids, water and ions - has been developed. It is established that local changes in the membrane environment play an important role in the binding of membrane-active peptides and peripherical membrane proteins, causing specific clustering of lipids and initiating the formation of defects in the membrane. It is shown for the first time that lipids make a significant contribution to the free energy of spontaneous dimerization of membrane proteins. The detailed balance of various energy contributions strongly depends on the composition of the membrane and the amino acid sequence of the protein. The assumption is made that the process of association of transmembrane alpha-helices in lipid bilayers has a predominantly entropic character.
Transmembrane domains of the most membrane proteins consist of single α-helices or their bundles. They take part in the functioning of receptors and ion channels and provide spatial structure formation. Thus, helix-helix interactions in lipid environment are involved in crucial processes of cell functioning. The concept of dimerization motifs representing protein-protein interactions as direct residue contacts is now replaced with the model of active membrane medium affecting embedded proteins. In the present work computer molecular dynamics simulations have been used to study the behavior of the transmembrane segment of glycophorin A and two artificial polypeptides (based on polyalanine and polyleucine) in hydrated lipid bilayers. It was demonstrated that both monomers and dimers present lipid interaction sites on the surface of helical transmembrane segments. In the case of glycophorin A monomer, the most prominent interaction site corresponds to the dimerization interface. The redistribution of bound lipid molecules during dimer formation stabilizes the dimeric state with the entropy contribution into the association free energy.