Several peptides, including penetratin and Tat, are known to translocate across the plasma membrane. Dynorphin opioid peptides are similar to cell-penetrating peptides in a high content of basic and hydrophobic amino acid residues. We demonstrate that dynorphin A and big dynorphin, consisting of dynorphins A and B, can penetrate into neurons and non-neuronal cells using confocal fluorescence microscopy/immunolabeling. The peptide distribution was characterized by cytoplasmic labeling with minimal signal in the cell nucleus and on the plasma membrane. Translocated peptides were associated with the endoplasmic reticulum but not with the Golgi apparatus or clathrin-coated endocytotic vesicles. Rapid entry of dynorphin A into the cytoplasm of live cells was revealed by fluorescence correlation spectroscopy. The translocation potential of dynorphin A was comparable with that of transportan-10, a prototypical cell-penetrating peptide. A central big dynorphin fragment, which retains all basic amino acids, and dynorphin B did not enter the cells. The latter two peptides interacted with negatively charged phospholipid vesicles similarly to big dynorphin and dynorphin A, suggesting that interactions of these peptides with phospholipids in the plasma membrane are not impaired. Translocation was not mediated via opioid receptors. The potential of dynorphins to penetrate into cells correlates with their ability to induce non-opioid effects in animals. Translocation across the plasma membrane may represent a previously unknown mechanism by which dynorphins can signal information to the cell interior.

We combine molecular simulations and ab initio calculations to investigate the permeation and separation of CO2/N2 in polymers of intrinsic microporosity (PIMs) with different functional groups (cyano, trifluoromethyl, phenylsulfone, and carboxyl). A robust equilibration protocol is proposed to construct model membranes with predicted densities very close to experimental data. The fractional free volumes (FFVs) in PIM-1 (with cyano), TFMPS-PIM (with both trifluoromethyl and phenylsulfone), and CX-PIM (with carboxyl) are 45.2%, 42.1%, and 38.7%, respectively. Hydrogen bonding is observed to form among carboxyl groups and contributes to the lowest FFV in CX-PIM. From wide-angle X-ray diffractions, the estimated d-spacing distances agree well with available experimental results, and the chain-to-chain distance in CX-PIM is the shortest among the three membranes. Ab initio calculations reveal that the interaction energies between the functional groups and CO2 decrease as carboxyl > phenylsulfone > cyano > trifluoromethyl; consistently, the simulated solubility coefficient of CO2 is the largest in CX-PIM. The simulated diffusion coefficient decreases with reducing FFV and correlates well with FFV. While the sorption selectivity of CO2/N2 increases in the order of PIM-1 < TFMPS-PIM < CX-PIM, the diffusion selectivity remains nearly constant; consequently, the permselectivity follows the same hierarchy as the solubility selectivity. This computational study provides microscopic insight into the role of functional groups in gas permeation and suggests that strong CO2-philic groups should be chosen to functionalize PIM membranes for high-efficiency CO2/N2 separation.

We report the first atomistic simulation study to characterize poly(ionic liquid) (PIL) membranes and examine their capability for post-combustion CO(2) capture. Four PILs based on 1-vinyl-3-butylimidazolium ([VBIM](+)) are examined with four different anions, namely bis(trifluoromethylsulfonyl)imide ([TF(2)N](-)), thiocyanate ([SCN](-)), hexafluorophosphate ([PF(6)](-)) and chloride ([Cl](-)). Gas molecules (CO(2) and N(2)) in [VBIM](+)-based PILs interact with polycations more strongly than with anions. Therefore, the role of anions in gas solubility is insignificant, which is in remarkable contrast to monomeric ILs. The solubilities predicted in the four PILs are close and in good agreement with available experimental data. The sorption, diffusion and permeation selectivities of CO(2)/N(2) predicted from simulation are consistent with experiment. Particularly, the diffusion selectivities are approximately equal to one, implying that CO(2)/N(2) separation is governed by sorption. This study provides atomistic insight into the mechanisms of gas sorption, diffusion and permeation in [VBIM](+)-based PILs and reveals that polycations play a dominant role in determining gas-membrane interaction and separation.

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Dynorphin A (Dyn A) is an endogenous ligand for kappa (κ) opioid receptors. To restrict the conformational mobility, we synthesized several cyclic Dyn A-(1-11)NH 2 analogs on solid phase utilizing ring-closing metathesis (RCM) between the side chains of allylglycine (AllGly) residues incorporated in positions 2, 5 and/or 8. Cyclizations between the side chains of AllGly gave reasonable yields (56-74%) of all of the desired cyclic peptides. Both the cis and trans isomers were obtained for all of the cyclic peptides, with the ratio of cis to trans isomers depending on the position and stereochemistry of the AllGly. Most of the cyclic Dyn A-(1-11)NH 2 analogs examined exhibit low nanomolar binding affinity for κ opioid receptors (K i = 0.84-11 nM). In two of the three cases the configuration of the double bond has a significant influence on the opioid receptor affinity and agonist potency. All of the peptides inhibited adenylyl cyclase (AC) activity in a concentration-dependent manner with full or close to full agonist activity. These potent Dyn A analogs are the first ones cyclized by RCM.