Kinetics of Trifluoromethane Clathrate Hydrate Formation from CHF3 Gas and Ice Particles.

We report the formation kinetics of trifluoromethane clathrate hydrate (CH) from less than 75 µm diameter ice particles and CHF3 gas. As previously observed for difluoromethane and propane hydrate formation, the initial stages of the reaction exhibit a strong negative correlation of the reaction rate with temperature, consistent with a negative activation energy of formation. The values obtained for trifluoromethane, ca. -6 kJ/mol (H2O), are similar to those for difluoromethane, even though the two molecules have different intermolecular interactions and sizes. The activation energy is lesser per mole of H2O, but greater per mole of guest molecule, than for propane hydrate, which has a different crystal structure. We propose a possible explanation for the negative activation barrier based on the stabilization of metastable structures at low temperature. A pronounced dependence of the formation kinetics on the gas flow rate into the cell is observed. At 253 K and a flow rate of 15 mmol/h, the stage II enclathration of trifluoromethane proceeds so quickly that the overpressure, the difference between the gas cell pressure and the hydrate vapor pressure, is only 0.06 MPa.

Prediction of clathrate structure type and guest position by molecular mechanics.

The clathrate hydrates occur in various types in which the number, size, and shape of the various cages differ. Usually the clathrate type of a specific guest is predicted by the size and shape of the molecular guest. We have developed a methodology to determine the clathrate type employing molecular mechanics with the MMFF force field employing a strategy to calculate the energy of formation of the clathrate from the sum of the guest/cage energies. The clathrate type with the most negative (most stable) energy of formation would be the type predicted (we mainly focused on type I, type II, or bromine type). This strategy allows for a calculation to predict the clathrate type for any cage guest in a few minutes on a laptop computer. It proved successful in predicting the clathrate structure for 46 out of 47 guest molecules. The molecular mechanics calculations also provide a prediction of the guest position within the cage and clathrate structure. These predictions are generally consistent with the X-ray and neutron diffraction studies. By supplementing the diffraction study with molecular mechanics, we gain a more detailed insight regarding the details of the structure. We have also compared MM calculations to studies of the multiple occupancy of the cages. Finally, we present a density functional calculation that demonstrates that the inside of the clathrates cages have a relatively uniform and low electrostatic potential in comparison with the outside oxygen and hydrogen atoms. This implies that van der Waals forces will usually be dominant in the guest-cage interactions.

Synthesis of a High Affinity Complementary Peptide-Polymer Nanoparticle (NP) Pair Using Phage Display.

Peptide-polymer complementary pairs can provide useful tools for isolating, organizing, and separating biomacromolecules. We describe a procedure for selecting a high affinity complementary peptide-polymer nanoparticle (NP) pair using phage display. A hydrogel copolymer nanoparticle containing a statistical distribution of negatively charged and hydrophobic groups was used to select a peptide sequence from a phage displayed library of >1010 peptides. The NP has low nanomolar affinity for the selected cyclic peptide and exhibited low affinity for a panel of diverse proteins and peptide variants. Affinity arises from the complementary physiochemical properties of both NP and peptide as well as the specific peptide sequence. Comparison of linear and cyclic variants of the peptide established that peptide structure also contributes to affinity. These findings offer a general method for identifying polymer-peptide complementary pairs. Significantly, precise polymer sequences (proteins) are not a requirement, a low information statistical copolymer can be used to select for a specific peptide sequence with affinity and selectivity comparable to that of an antibody. The data also provides evidence for the physiochemical and structural contributions to binding. The results confirm the utility of abiotic, statistical, synthetic copolymers as selective, high affinity peptide affinity reagents.

Propane Clathrate Hydrate Formation Accelerated by Methanol.

The role of methanol as both an inhibitor and a catalyst for the formation of clathrate hydrates (CHs) has been a topic of intense study. We report a new quantitative study of the kinetics of propane CH formation at 253 K from the reaction of propane gas with <75 µm ice particles that have been doped with varying amounts of methanol. We find that methanol significantly accelerates the formation reaction with quite small doping quantities. Even for only 1 methanol molecule per 10 000 water molecules, the maximum uptake rate of propane into CHs is enhanced and the initiation pressure is reduced. These results enable more efficient production of CHs for gas storage. This remarkable acceleration of the CH formation reaction by small quantities of methanol may place constraints on the mechanism of the inhibition effect observed under other conditions, usually employing much larger quantities of methanol.

Synthesis of 1-boraadamantaneamine derivatives with selective astrocyte vs C6 glioma antiproliferative activity. A novel class of anti-hepatitis C agents with potential to bind CD81.

A variety of amine complexes with 1-boraadamatane were synthesized and subsequently evaluated for an antiproliferative effect on CD81-enriched cell lines to provide evidence for binding and activation of CD81. CD81 is a member of the tetraspanin family of membrane proteins found in all cell lineages in the liver. CD81 signals for antiproliferation when bound by antibodies. It is known that the HCV-E2 envelope glycoprotein binds to the CD81 protein. While it is unclear whether virus entry into host cells is directly linked to virus attachment via CD81 for HCV, this step in the viral life cycle has recently proven to be an effective point of attack for other viruses including HIV and rhinoviruses. The aim of the current study concerns the synthesis of amantidine analogues by appending primary amines to 1-boraadamantane to evaluate such compounds for CD81-dependent antiproliferation of CD81-enriched cell lines (astrocyte) vs CD81-deficient cell lines (C6 glioma). If the antiproliferative effect of these amantidine analogues proves to be an effect of binding and activating CD81, then these compounds may have the potential to prevent or treat HCV infections. Each compound's potential for preventive and therapeutic activity stems from the compound's potential to block viral attachment, virus-cell fusion, or virus entry into host cells or to counter potential mechanisms of HCV immune evasion. Out of a library of over 500 compounds, including randomly selected small molecules and rationally designed small molecules, only the 1-boraadamantaneamine compounds and structurally similar analogues display a significant antiproliferative effect on the CD81-enriched astrocytes relative to the CD81-deficient cell lines. In fact, 1-boraadamantane.l-phenylalanine methyl ester complex (5), 1-boraadamantane.ethanolamine complex (8), and (S)-2-[(adamantane-1-carbonyl)amino]-3-phenylpropionic acid (15) show a dose-dependent, astrocyte-selective antiproliferative activity in the concentration range 0.1-10 microM. This is consistent with the binding and activation of CD81 and represents a 2-fold improvement compared to the clinically prescribed anti-HCV agent, amantidine, in the same concentration range. Consequently, the 1-boraadamantaneamine derivatives present a promising lead in the development of small molecules with potential to bind to CD81 and treat HCV infections.