Oxytocin (OT) is a neurohypophysial hormone, which acts both on the peripheral tissues (hormonal), and as a neurotransmitter in the brain. It plays an important role in the control of the uterine contractions during labor, secretion of milk and in many social and behavioural functions. OT accomplishes its functions via interaction with specific oxytocin receptors (OTRs), which belong to the rhodopsin type (class I) group of G-protein coupled receptors (GPCRs). Data from experimental and theoretical studies have shown that the binding of divalent zinc ion to the oxytocin molecule drastically alters its conformation and ensures its correct location in the active center of the receptor. The formation of a stable octahedral complex between oxytocin and divalent zinc ion in an aqueous solution is an important condition necessary for the binding of the hormone to its receptor. So far however, in crystallographic databases there isn't yet information about the 3D structure of the complex. The aim of our study was to create a rigid structure between the human hormone oxytocin and divalent zinc ion and confirmation of its stability by molecular dynamics (MD) simulations. To achieve this goal a computer model of the hormone-metal complex was built by bonded approach. We used CHARMM 36 force field and artificial bonds, to produce a structure with octahedral orientation of the six carbonyl backbone oxygens of the oxytocin molecule, surrounding the zinc ion. The Gromacs software package was used to check the stability of the constructed oxytocin-zinc ion system by conducting 50 ns simulations in aqueous solution.

Abstract.A novel methodology for the synthesis of sulfo-and oxy-modified amino acid analogues of arginine (Arg) has been developed using both conventional and polymer assisted synthesis from ready available amino acid precursor. Introduction of guanidine group was made also by the MWA synthesis. The in vitro inhibitory effect of the amino acid analogues on the growth of murine erythroleukemia cells, clone F4N in culture was also studied. (doi: 10.5562/cca1780)

The extremely controversial conclusions about the function of human interferon-gamma (hIFNγ) C-terminus as well as the lack of a consistent model explaining its role in the receptor binding prompted us to scrutinize the interaction of hIFNγ with its extracellular receptor hIFNGR1 in different scenarios by means of molecular dynamics simulations. We find that the two molecules alone fail to form a stable complex but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity essay on cells depleted from surface sulfation confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFNγ signalling.

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Human interferon-gamma (hIFNγ) is a crucial signaling molecule with an important role in the initialization and development of the immune response of the host. However, its aberrant activity is also associated with the progression of a multitude of autoimmune and other diseases, which determines the need for effective inhibitors of its activity. The development of such treatments requires proper understanding of the interaction of hIFNγ to its cell-surface receptor hIFNGR1. Currently, there is no comprehensive model of the mechanism of this binding process. Here, we employ molecular dynamics simulations to study on a microscopic level the process of hIFNγ–hIFNGR1 complex formation in different scenarios. We find that the two molecules alone fail to form a stable complex, but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity assay on cells depleted from cell-surface heparan sulfate (HS) sulfation together with the phosphorylation levels of the signal transducer and activator of transcription STAT1 confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFNγ signalling.