Water molecules in the narrow cylindrical pore of a (6,6) carbon nanotube form single-file chains with their dipoles collectively oriented either up or down along the tube axis. We study the interaction of such water chains with homogeneous electric fields for finite closed and infinite periodically replicated tubes. By evaluating the grand-canonical partition function term-by-term, we show that homogeneous electric fields favor the filling of previously empty nanotubes with water from the bulk phase. A two-state description of the collective water dipole orientation in the nanotube provides an excellent approximation for the dependence of the water-chain polarization and the filling equilibrium on the electric field. The energy and entropy contributions to the free energy of filling the nanotube were determined from the temperature dependence of the occupancy probabilities. We find that the energy of transfer depends sensitively on the water-tube interaction potential, and that the entropy of one-dimensionally ordered water chains is comparable to that of bulk water. We also discuss implications for proton transfer reactions in biology.

We explore the structure and thermodynamics of water clusters confined in nonpolar cavities. By calculating the grand-canonical partition function term by term, we show that small nonpolar cavities can be filled at equilibrium with highly structured water clusters. The structural and thermodynamic properties of these encapsulated water clusters are similar to those observed experimentally in the gas phase. Water filling is highly sensitive to the size of the cavity and the strength of the interactions with the cavity wall. Water penetration into pores can thus be modulated by small changes in the polarity and structure of the cavity. Implications on water penetration into proteins are discussed.grand canonical ensemble ͉ hydrophobic interactions ͉ fullerenes ͉ free energy of transfer ͉ configurational-specific heat H ydrophobic literally means water repelling. So are nonpolar cavities hydrophobic, i.e., devoid of water? Answering this question profoundly impacts our understanding of the role of water in protein function. Although some weakly polar cavities created inside proteins by mutations were indeed found to be empty (1), recent studies using crystallography (2-4), NMR (5, 6), and simulations (7) show that water molecules may be present at least transiently. Evidence for a functional role of water in the nonpolar interior of proteins is also accumulating. Water has been implicated as the mediator for proton transfer through the nonpolar interior channels of the proton pumps cytochrome c oxidase (8) and bacteriorhodopsin (9), and the monooxygenase cytochrome P450 (10, 11), with water detected in trapped intermediates (9, 10), but empty channels in crystal structures of the resting enzymes.Water permeation of carbon nanotubes (12-14) and the dewetting of hydrophobic surfaces (15-17) have been studied recently, but the thermodynamic driving forces for water filling nonpolar cavities remain poorly understood. The loss of hydrogen-bond energy should render the transfer of a single water molecule into a nonpolar environment energetically unfavorable (18). Moreover, multiple water molecules confined into narrow spaces will form highly ordered structures, resulting in unfavorable entropies of transfer. However, mounting experimental evidence for water penetrating into weakly polar cavities in the protein interior (2-6, 9, 10, 19) suggests that this simple reasoning must be incomplete.To investigate the hydration of nonpolar cavities, we reverse the extensively studied process of nonpolar solvation in water (20, 21) and study instead the more poorly understood transfer of water into a nonpolar environment (18). We demonstrate that water can fill nonpolar cavities at ambient conditions, with entropy and ''weak'' van der Waals interactions playing a critical role, and that the strong water-hydrogen-bond interactions lead to the formation of unique water clusters similar in topology to the gas-phase structures detected spectroscopically (22-27).We study the stability and structure of water in nonpolar cavities of varyi...

Molecular dynamics simulations of water at 298 K and 1 atm of pressure are used to investigate the electric-field dependence of the density and polarization density of water between two graphite-like plates of different sizes (9.8 x 9.2 and 17.7 x 17.2 A) in an open system for plate separations of 8.0, 9.5, and 16.4 A. The interactions with water were tuned to "hard-wall-like" and "normal" C-O hydrophobic potentials. Water between the larger plates at 16.4 A separation is layered but is metastable with respect to capillary evaporation at zero field (Bratko, D.; Curtis, R. A.; Blanch, H. W.; Prausnitz, J. M. J. Chem. Phys. 2001, 115, 3873). Applying a field decreases the density of the water between the plates, in apparent contradiction to thermodynamic and integral equation theories of bulk fluid electrostriction that ignore surface effects, rendering them inapplicable to finite-sized films of water between hydrophobic plates. This suggests that the free energy barrier for evaporation is lowered by the applied field. Water, between "hard-wall-like" plates at narrower separations of 9.5 A and less, shows a spontaneous but incomplete evaporation at zero field within the time scale of our simulation. Evaporation is further enhanced by an electric field. No such evaporation occurs, on these time scales, for the smaller plates with the "hard-wall-like" potential at a separation of 8.0 A at zero field, signaling a crossover in behavior as the plate dimension decreases, but the water density still diminishes with increasing field strength. These observations could have implications for the behavior of thin films of water between surfaces in real physical and biological systems.

Transition state search is at the center of multiple types of computational chemical predictions related to mechanistic investigations, reactivity and regioselectivity predictions, and catalyst design. The process of finding transition states in practice is, however, a laborious multistep operation that requires significant user involvement. Here, we report a highly automated workflow designed to locate transition states for a given elementary reaction with minimal setup overhead. The only essential inputs required from the user are the structures of the separated reactants and products. The seamless workflow combining computational technologies from the fields of cheminformatics, molecular mechanics, and quantum chemistry automatically finds the most probable correspondence between the atoms in the reactants and the products, generates a transition state guess, launches a transition state search through a combined approach involving the relaxing string method and the quadratic synchronous transit, and finally validates the transition state via the analysis of the reactive chemical bonds and imaginary vibrational frequencies as well as by the intrinsic reaction coordinate method. Our approach does not target any specific reaction type, nor does it depend on training data; instead, it is meant to be of general applicability for a wide variety of reaction types. The workflow is highly flexible, permitting modifications such as a choice of accuracy, level of theory, basis set, or solvation treatment. Successfully located transition states can be used for setting up transition state guesses in related reactions, saving computational time and increasing the probability of success. The utility and performance of the method are demonstrated in applications to transition state searches in reactions typical for organic chemistry, medicinal chemistry, and homogeneous catalysis research. In particular, applications of our code to Michael additions, hydrogen abstractions, Diels-Alder cycloadditions, carbene insertions, and an enzyme reaction model involving a molybdenum complex are shown and discussed.

A number of situations ranging from protein folding in confined spaces, lubrication in tight spaces, and chemical reactions in confined spaces require understanding water-mediated interactions. As an illustration of the profound effects of confinement on hydrophobic and ionic interactions we investigate the solvation of methane and methane decorated with charges in spherically confined water droplets. Free energy profiles for a single methane molecule in droplets, ranging in diameter (D) from 1 to 4 nm, show that the droplet surfaces are strongly favorable as compared to the interior. From the temperature dependence of the free energy in D = 3 nm, we show that this effect is entropically driven. The potentials of mean force (PMFs) between two methane molecules show that the solvent separated minimum in the bulk is completely absent in confined water, independent of the droplet size since the solute particles are primarily associated with the droplet surface. The tendency of methanes with charges (M q+ and M q− with q + = |q − | = 0.4e, where e is the electronic charge) to be pinned at the surface depends dramatically on the size of the water droplet. When D = 4 nm, the ions prefer the interior whereas for D < 4 nm the ions are localized at the surface, but with much less tendency than for methanes. Increasing the ion charge to e makes the surface strongly unfavorable. Reflecting the charge asymmetry of the water molecule, negative ions have a stronger preference for the surface compared to positive ions of the same charge magnitude. With increasing droplet size, the PMFs between M q+ and M q− show decreasing influence of the boundary due to the reduced tendency for surface solvation. We 1 also show that as the solute charge density decreases the surface becomes less unfavorable. The implications of our results for the folding of proteins in confined spaces are outlined.

We applied density functional theory to investigate the mixed aldol condensation of acetone and formaldehyde in acid zeolites HZSM-5 and HY, as a prototypical bond-forming reaction in biofuel production. We modeled the acid-catalyzed reaction in HZSM-5 and HY in two steps: keto− enol tautomerization of acetone and bimolecular condensation between formaldehyde and the acetone enol. For both acid zeolites, the keto−enol tautomerization of acetone was found to be the rate-determining step, consistent with the accepted mechanism in homogeneous acid-catalysis. Convergence studies of the activation energy for keto−enol tautomerization, with respect to cluster sizes of HZSM-5 and HY, exhibit rather different convergence properties for the two zeolites. The keto−enol activation energy was found to converge in HY to ∼20 kcal/mol for a cluster with 11 tetrahedral atoms (11T cluster), which does not complete the HY supercage. In contrast, the activation energy for HZSM-5 reaches an initial plateau at a value of ∼28 kcal/mol for clusters smaller than 20T and then converges to ∼20 kcal/mol for clusters of size 26T or greater, well beyond the completion of the HZSM-5 pore. As such, completing a zeolite pore surrounding a Brønsted acid site may be insufficient to converge activation energies; instead, we recommend an approach based on converging active-site charge.

Confinement effects on protein stability are relevant in a number of biological applications ranging from encapsulation in the cylindrical cavity of a chaperonin, translocation through pores, and structure formation in the exit tunnel of the ribosome. Consequently, free energies of interaction between amino acid side chains in restricted spaces can provide insights into factors that control protein stability in nanopores. Using all-atom molecular dynamics simulations, we show that 3 pair interactions between side chains-hydrophobic (Ala-Phe), polar (Ser-Asn) and charged (Lys-Glu)-are substantially altered in hydrophobic, water-filled nanopores, relative to bulk water. When the pore holds water at bulk density, the hydrophobic pair is strongly destabilized and is driven to large separations corresponding to the width and the length of the cylindrical pore. As the water density is reduced, the preference of Ala and Phe to be at the boundary decreases, and the contact pair is preferred. A model that accounts for the volume accessible to Phe and Ala in the solvent-depleted region near the pore boundary explains the simulation results. In the pore, the hydrogen-bonded interactions between Ser and Asn have an enhanced dependence on their relative orientations, as compared with bulk water. When the side chains of Lys and Glu are restrained to be side by side, parallel to each other, then salt bridge formation is promoted in the nanopore. Based on these results, we argue and demonstrate that for a generic amphiphilic sequence, cylindrical confinement is likely to enhance thermodynamic stability relative to the bulk. confinement effects on protein stability ͉ hydrophobic interactions ͉ potentials of mean force ͉ water in pores

We performed kinetics experiments and quantum calculations to investigate the reaction of furan to benzofuran catalyzed by the acidic zeolite HZSM-5, which is a key step in the conversion of biomass to biofuels through catalytic fast pyrolysis. The reaction was studied experimentally by placing the zeolite in contact with solution-phase furan and detecting the benzofuran product over the temperature range 270−300 °C, yielding an apparent activation energy of 72 ± 3 kJ/mol. The reaction was modeled in gas and zeolite phases to determine the energetics of the following two competing pathways: a Diels−Alder mechanism often assumed in interpretations of experimental data and a ring-opening pathway predicted by the chemoinformatic software RING. Quantum calculations on the zeolite/guest system were performed using the ONIOM embedded cluster approach. We computed the energetics of reactants, products, and all intermediate steps. Locating relevant transition states fell beyond our computational resources because of system size and the ruggedness of the energy landscape. The Diels−Alder mechanism in the gas phase was found to pass through a high-energy intermediate roughly 380 kJ/mol above the reactant energy, which reduces to approximately 200 kJ/ mol in HZSM-5. In contrast, the ring-opening mechanism passes through a gas-phase intermediate roughly 500 kJ/mol above the reactant energy, which falls to approximately 50 kJ/mol in HZSM-5. The energy of the ring-opening mechanism over HZSM-5 fits into the experimentally determined energy "budget" of 72 ± 3 kJ/mol. These experimental and computational results highlight the importance of the ring-opening mechanism for this key step in making biofuels. Our results strongly indicate that, in the cavities of HZSM-5, the condensation of two furan molecules to form benzofuran and water does not proceed by a Diels− Alder reaction between the reactants.