Biochemistry of opioid (morphine) receptors : binding, structure and molecular modelling

Morphine is the most widely used compound among narcotic analgesics and remains the gold standard when the effects of other analgetic drugs are compared. The most characteristic effect of morphine is the modulation of pain perception resulting in an increase in the threshold of noxious stimuli. Antinociception induced by morphine is mediated via opioid receptors, namely the μ-type opioid receptor. Apart from the μ-opioid receptor, two other classical opioid receptors κ- and δ- and one non-classical opioid receptor, the nociceptin receptor was discovered and cloned so far. At the same time endogenous opioids were also discovered, such as enkephalins, endorphins, and dynorphins. The opioid receptors together with the endogenous opioids form the so called endogenous opioid system, which is highly distributed throughout the body and apart from analgesia it has several other important physiological functions. In this article we will review the historical milestones of opioid research − in detail with morphine. The review will also cover the upmost knowledge in the molecular structure and physiological effects of opioid receptors and endogenous opioids and we will discuss opioid receptor modelling − a rapidly evolving field in opioid receptor research

Modeling the Effect on a Novel Fungal Peptaibol Placed in an All-Atom Bacterial Membrane Mimicking System via Accelerated Molecular Dynamics Simulations

We previously reported on a novel peptaibol, named Tripleurin XIIc (TPN), an 18-residue long sequence produced by the fungus Trichoderma pleuroti. We elucidated its 3D structure via classical and accelerated molecular dynamics simulation (aMD) methods and reported the folding dynamics of TPN in water and chloroform solvents. Peptaibols, in general, are insoluble in water, as they are amphipathic and may prefer hydrophobic environments like transmembrane regions. In this study, we attempted to use aMD simulations to model an all-atom bacterial membrane system while placing a TPN molecule in its vicinity. The results highlighted that TPN was able to introduce some disorder into the membrane and caused lipid clustering. It could also enter the transmembrane region from the water-bilayer interface. The structural dynamics of TPN in the transmembrane region revealed a single energetically stable conformation similar to the one obtained from water and chloroform solvent simulations reported by us previously. However, this linear structure was found to be at the local energy minimum (stable) in water but at a metastable intermediate state (higher energy) in chloroform. Therefore, it could be said that the water solvent can be successfully used for folding simulations of peptaibols

What have we learned from two-pore potassium channels? Their molecular configuration and function in the human heart

Two-pore domain potassium channels (K2P) control excitability, stabilize the resting membrane potential below firing threshold, and accelerate repolarisation in different cells. Until now, fifteen different genes for the six K2P channel subfamily were cloned. The pore-forming part is translated from two genes and they are built up from a dimer of two two-unit transmembrane domains functioning with a wide spectrum of physiological profiles. K2P ion channels were discovered in the last two decades and gave novel opportunity to recognize the complex molecular mechanism of the potassium ion flux, and may lead to the design of individual drug targeting in the future. In this review, we summarise the structure, function, channelopathies and pharmacological silhouette of the two-pore potassium channels in the human tissues. In addition, we present the computer model of the partially reconstructed wild type K2P1/TWIK1 lacking the intracellular C and N terminal loop