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Information × Registration Number 0216U001755, 0113U001516 , R & D reports Title The study of peculiarities of antimicrobial peptides interactions with targets popup.stage_title Head Lisnyak Yuriy Volodimirovich, Registration Date 06-04-2016 Organization The Mechnikov Research Institute of microbiology and immunology at Kharciv popup.description2 The aim of study: ascertainment of the peculiarities of intermolecular interactions of antimicrobial peptides with their biotargets to determine the key structural features of their molecules which stipulate therapeutic efficacy of the peptide antibiotics group. The tasks of study: to investigate ligand-receptor interactions of polymyxin with its three cell targets: lipopolysaccharide component of the outer membrane of gram-negative bacterium, lipid А; with phospholipids of the inner membrane of gram-negative bacterium and with the surface receptor of the epithelium of human kidney proximal tubules, megalin; to reveal the structural features of polymyxins molecules which stipulate their antimicrobial activity and their nephrotoxicity. Objects of study: the complexes of polymyxin and its derivatives with lipid A; the complexes of polymyxin with dodecylphosphocholine and sodium dodecylsulfate micelles, with phosphatidylcholine and phosphatidylethanolamine bilayer membranes; polymyxin complexes with ligand-binding domens of low-density lipoprotein receptor (LDLR). Subject of study: intermolecular interactions and peculiarities of polymyxin B binding with lipid A, with model membranes and with megalin; structural aspects of polymyxins antimicrobial and nephrotoxic action. Methods: methods of bioinformatics and molecular modeling : minimization, simulated annealing, ligand docking into the receptor, molecular dynamics. Results: There was shown the crucial role of the residues of di-amino-butane acid (Dab residues) at positions 1, 3, 5, 8 and 9 of polymyxin for its binding with lipid A. The peptide interaction with a sodium dodecylsulfate (SDS) micelle or a zwitterionic phosphatidyl ethanolamine (PEA) lipid bilayer, mimetics of a membrane of gram-negative bacteria, occurs due to electrostatic and/or hydrogen-bonding interactions of its protonated and polar groups with charged and polar groups of SDS micelle or polar groups of PEA lipid layer. The peptide interaction with zwitterionic dodecylphosphocholine (DPC) micelle and with zwitterionic phosphatidylcholine (PC) lipid bilayer, mimetics of cell membrane of a human erythrocyte, takes place due to hydrophobic interactions of Phe, Leu and methyloctanoyl. The polymyxin binding is stronger with PEA membrane than with PC one. There was shown the possibilty to form a stable complex of polymyxin B with megalin ligand-binding repeats in accordance with a universal mechanism of cationic ligand binding by ligand-binding repeats of receptors of LDLR-family. There was shown that polymyxin interacts with megalin stronger than its NAB-derivative. There were revealed the structural prerequisites for these interaction differences. Product Description popup.authors Лісняк Ю.В. Носальська Т.М. popup.nrat_date 2020-04-02 Close