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Ligand docking is a widely used tool for lead discovery and binding mode prediction based drug discovery. The greatest challenges in docking occur when the receptor significantly reorganizes upon small molecule binding, thereby requiring an induced fit docking (IFD) approach in which the receptor is allowed to move in order to bind to the ligand optimally. IFD methods have had some success but suffer from a lack of reliability. Complementing IFD with all-atom molecular dynamics (MD) is a straightforward solution in principle but not in practice due to the severe time scale limitations of MD. Here we introduce a metadynamics plus IFD strategy for accurate and reliable prediction of the structures of protein–ligand complexes at a practically useful computational cost. Our strategy allows treating this problem in full atomistic detail and in a computationally efficient manner and enhances the predictive power of IFD methods. We significantly increase the accuracy of the underlying IFD protocol across a large data set comprising 42 different ligand–receptor systems. We expect this approach to be of significant value in computationally driven drug design.

Computer simulations are used to determine the free energy landscape for the binding of the anticancer drug Dasatinib to its src kinase receptor and show that before settling into a free energy basin the ligand must surmount a free energy barrier. An analysis based on using both the ligand-pocket separation and the pocket-water occupancy as reaction coordinates shows that the free energy barrier is a result of the free energy cost for almost complete desolvation of the binding pocket. The simulations further show that the barrier is not a result of the reorganization free energy of the binding pocket. Although a continuum solvent model gives the location of free energy minima, it is not able to reproduce the intermediate free energy barrier. Finally, it is shown that a kinetic model for the on rate constant in which the ligand diffuses up to a doorway state and then surmounts the desolvation free energy barrier is consistent with published microsecond time-scale simulations of the ligand binding kinetics for this system [Shaw, D. E. et al. J. Am. Chem. Soc.2011, 133, 9181−9183].

Acetonitrile confined in silica nanopores with surfaces of varying functionality is studied by means of molecular dynamics simulation. The hydrogen-bonding interaction between the surface and the liquid is parametrized by means of first-principles molecular dynamics simulations. It is found that acetonitrile orders into bilayer like structures near the surface, in agreement with prior simulations and experiments. A newly developed method is applied to calculate relevant time correlation functions for molecules in different layers of the pore. This method takes into account the short lifetimes of the molecules in the layers. We compare this method with prior techniques that do not take this lifetime into account and discuss their pitfalls. We show that in agreement with experiment, the dynamics of the system may be described by a two population model that accounts for bulk-like relaxation in the center and frustrated dynamics near the surface of the pore. Specific hydrogen-bonding interactions are found to play a large role in engendering this behavior.

Calculation of protein−ligand binding affinities continues to be a hotbed of research. Although many techniques for computing protein−ligand binding affinities have been introducedranging from computationally very expensive approaches, such as free energy perturbation (FEP) theory, to more approximate techniques, such as empirically derived scoring functions, which, although computationally efficient, lack a clear theoretical basisthere remains a pressing need for more robust approaches. A recently introduced technique, the displaced-solvent functional (DSF) method, was developed to bridge the gap between the high accuracy of FEP and the computational efficiency of empirically derived scoring functions. In order to develop a set of reference data to test the DSF theory for calculating absolute protein−ligand binding affinities, we have pursued FEP theory calculations of the binding free energies of a methane ligand with 13 different model hydrophobic enclosures of varying hydrophobicity. The binding free energies of the methane ligand with the various hydrophobic enclosures were then recomputed by DSF theory and compared with the FEP reference data. We find that the DSF theory, which relies on no empirically tuned parameters, shows excellent quantitative agreement with the FEP. We also explored the ability of buried solvent accessible surface area and buried molecular surface area models to describe the relevant physics and find the buried molecular surface area model to offer superior performance over this data set.

Multiple time scale methodologies have gained widespread use in molecular dynamics simulations and are implemented in a variety of ways across numerous packages. However, performance of the algorithms depends upon the details of the implementation. This is particularly important in the way in which the nonbonded interactions are partitioned. In this work, we show why some previous implementations give rise to energy drifts, and how this can be corrected. We also provide a recipe for using multiple time step methods to generate stable trajectories in large scale biomolecular simulations, where long trajectories are needed.

Because of its fundamental importance to molecular biology, great interest has continued to persist in developing novel techniques to efficiently characterize the thermodynamic and structural features of liquid water. A particularly fruitful approach, first applied to liquid water by Lazaridis and Karplus, is to use molecular dynamics or Monte Carlo simulations to collect the required statistics to integrate the inhomogeneous solvation theory equations for the solvation enthalpy and entropy. We here suggest several technical improvements to this approach, which may facilitate faster convergence and greater accuracy. In particular, we devise a nonparametric kth nearest-neighbors (NN)-based approach to estimate the water−water correlation entropy, and we suggest an alternative factorization of the water−water correlation function that appears to more robustly describe the correlation entropy of the neat fluid. It appears that the NN method offers several advantages over the more common histogram-based approaches, including much faster convergence for a given amount of simulation data; an intuitive error bound that may be readily formulated without resorting to block averaging or bootstrapping; and the absence of empirically tuned parameters, which may bias the results in an uncontrolled fashion.

We study by molecular dynamics simulations the wetting/dewetting transition and the dependence of the free energy on the distance between plates that contain both hydrophobic and hydrophilic particles. We show that dewetting is very sensitive to the distribution of hydrophobic and hydrophilic domains. In particular, we find that plates characterized by a large domain of hydrophobic sites induce a dewetting transition and an attractive solvent-induced interaction. On the other hand, a homogeneous distribution of the hydrophobic and hydrophilic particles on the plates prevents the dewetting transition and produces a repulsive solvent-induced interaction. We also present results for a system resembling a “Janus interface” in which one plate consists of hydrophobic particles and the other consists of hydrophilic particles showing that the interplate gap remains wet until steric constraints at small separations eject the water molecules. Our results indicate that the Cassie equation, for the contact angle of a heterogeneous plate, can not be used to predict the critical distance of dewetting. These results indicate that hydrophobic interactions between nanoscale surfaces with strong large length-scale hydrophobicity can be highly cooperative and thus they argue against additivity of the hydrophobic interactions between different surface domains in these cases. These findings are pertinent to certain protein−protein interactions where additivity is commonly assumed.

The phase ordering of 1-bromoeicosane (C20H41Br) at the liquid-graphite and vacuum-graphite interfaces is examined through a joint experimental (part I) and theoretical effort (part II). The stable morphologies under solvent and ultrahigh vacuum conditions are revealed by STM experiments to be the head-to-head structures with 90° and 60° lamella−backbone angles, respectively. At 90° and 60° close packing is attained, independent of the corrugation of the graphite lattice. The potential energy of the minimized 60° structure is slightly lower than that of the 90° structure under vacuum conditions. In addition, the basin of the potential energy surface about the 90° form is very narrow. All-atom molecular dynamics simulations depict a 90°-to-60° phase transition in vacuum. Both morphologies are stable when an explicit solvent model is included. We speculate that the choice of the 90° form under solvent is driven by symmetry considerations and the self-assembly pathway. For example, the 90° structure may serve as a superior template for solvent capping. An implicit solvent model fails to stabilize the 90° form; however, it does lower the potential energy of this structure relative to the 60° geometry.

Self-assembled monolayers of 1-bromoeicosane (BrC20H41) have been investigated at the vacuum−graphite and liquid−graphite interfaces using scanning tunneling microscopy (STM) (Part I) and theory (Part II). Under ultrahigh vacuum conditions at 80 K, STM images show 1-bromoeicosane in a lamellar assembly structure where individual molecules are predominantly arranged with their bromine groups pointed head-to-head with a 66 ± 3° angle between the lamella direction and the molecular backbone axis. A significant degree of disorder is observed under vacuum conditions, in which head-to-tail defects are interspersed throughout the film. When 1-bromoeicosane monolayers are formed and imaged in equilibrium with solution at ∼290 K, the molecules again pack with their bromines oriented head-to-head but shift to form a nearly rectangular array. Subtle changes are observed depending on the solvent utilized, with the lamella−backbone angle varying between 81 ± 3° and 90 ± 2°, and the corresponding intermolecular spacing ranging from 0.36 ± 0.02 to 0.46 ± 0.05 nm. The differences between the vacuum- and solution-based packing, as well as the possibility of two different packing structures occurring in solution, are discussed in light of the joint experimental and theoretical analysis.

The structural properties of self-assembled monolayers of short 1-bromoalkanes and n-alkanes on graphite were investigated by a combination of ultrahigh vacuum scanning tunneling microscopy (UHV-STM) at 80 K and theoretical methods. STM images of 1-bromohexane reveal a lamellar packing structure in which the molecules form a 57° ± 3° lamella-molecular backbone angle and a head-to-head assembly of the bromine atoms (Müller, et al. Proc. Natl. Acad. Sci. U.S.A.2005, 102, 5315). STM images of 1-bromoheptane also show a head-to-head 60° ± 3° lamella-molecular backbone pattern; however, the molecules pack in a herringbone structure. The odd/even chain-length alternation in the monolayer morphologies of 1-bromoalkanes is similar to that observed for the self-assembly of short n-alkanes on graphite, suggesting that the bromine atom acts effectively as an extension of the carbon backbone. The analogy, however, is incomplete. Odd and even short n-alkanes (hexane, heptane, octane) display 60° herringbone and rectangular (not 60°) lamella-molecular backbone configurations, respectively. The balance of intermolecular forces and packing considerations responsible for this odd/even alternation in monolayer morphology for short 1-bromoalkanes on graphite is examined here according to classical molecular dynamics simulations and in light of the structural properties of analogous n-alkane assemblies.

The morphological enantio-identity of racemic (R)/(S)-2-bromohexadecaonic acid self-assemblies on graphite is examined according to molecular dynamics simulations of the optimized potential for liquid simulations (OPLS) force field. Racemic (R)/(S)-2-bromohexadecaonic acid segregates at the graphite−solvent interface into coexisting domains characterized by approximately 50° clockwise and 50° counter-clockwise lamellae-trough angles. The “upward” orientation (away from the graphite surface) of bromine atoms has been observed experimentally to be thermodynamically more stable under solvent for a wide range of bromo-substituted organic molecules, suggesting that the domains of racemic (R)/(S)-2-bromohexadecaonic acid observed by scanning tunneling microscopy under phenyl octane solvent consist of pure enantiomers. Our calculations, performed under vacuum conditions, suggest a competition between the stability gained by mixing “upward” and “downward” pairs of (R) and (S) enantiomers and the symmetry breaking that favors the “upward” orientation of the bromine atoms at the graphite−solvent interface. The calculations indicate that racemic (R)/(S)-2-bromohexadecaonic acid is likely to form enantio-mixed domains at the graphite−vacuum interface. The possibility that the domains formed by racemic (R)/(S)-2-bromohexadecaonic acid at the graphite−solvent interface are not enantio-pure is discussed in this paper.

We present results of developing a methodology suitable for producing molecular mechanics force fields with explicit treatment of electrostatic polarization for proteins and other molecular system of biological interest. The technique allows simulation of realistic‐size systems. Employing high‐level ab initiodata as a target for fitting allows us to avoid the problem of the lack of detailed experimental data. Using the fast and reliable quantum mechanical methods supplies robust fitting data for the resulting parameter sets. As a result, gas‐phase many‐body effects for dipeptides are captured within the average RMSD of 0.22 kcal/mol from their ab initiovalues, and conformational energies for the di‐ and tetrapeptides are reproduced within the average RMSD of 0.43 kcal/mol from their quantum mechanical counterparts. The latter is achieved in part because of application of a novel torsional fitting technique recently developed in our group, which has already been used to greatly improve accuracy of the peptide conformational equilibrium prediction with the OPLS‐AA force field.1 Finally, we have employed the newly developed first‐generation model in computing gas‐phase conformations of real proteins, as well as in molecular dynamics studies of the systems. The results show that, although the overall accuracy is no better than what can be achieved with a fixed‐charges model, the methodology produces robust results, permits reasonably low computational cost, and avoids other computational problems typical for polarizable force fields. It can be considered as a solid basis for building a more accurate and complete second‐generation model. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 1515–1531, 2002

In the interests of making chemistry more environmentally friendly, room-temperature ionic liquids are currently being investigated as alternative solvents in industry and academia. In this paper, we present molecular dynamics simulations of 1-buthyl-3 methylimidazolium hexafluorophosphate ([bmim][PF6]). We compute radial distribution functions, average density, and mean-square displacements for the individual ions. With this information, diffusion coefficients are calculated and conductivities are estimated using the Nernst−Einstein relation. The time history of the mean-square displacement of the ions appears to indicate that the system exhibits complex dynamics with at least two different time scales for diffusion. We model this behavior using a generalized Langevin approach. Results compare well with experimental data reported in the literature.

The dynamics of folding and unfolding of secondary structural motifs found in proteins is crucial to understanding the protein folding problem. In this paper we study the short-time dynamics of loop unfolding and hydrogen bond formation and breaking in the alanine pentapeptide at room temperature, using several constant-energy molecular dynamics simulations of about 4 ns of duration. We analyze the results in terms of time histories of “core” α-carbon dihedral angles. We also perform a principal component analysis of the data. We find that the time scale for a considerable deformation of the dihedral angles formed by the α-carbons is on the order of 1 ns whereas hydrogen bonds seem to break and form on a shorter time scale.

In this paper we develop a “diatomic in molecules semiempirical ligand field” (DIMSELF) method to calculate ground and excited many-body potential energy surfaces for an arbitrary transition metal ion in an arbitrary complex system. This method is not restricted to a high-symmetry environment and is meant to be inexpensive and suitable for nonadiabatic excited states dynamics on-the-fly. Within the approximations employed, the method includes full CI (configuration interaction) and SO (spin−orbit) interactions, essential to the description of nonradiative transitions such as those of myoglobin in the presence of carbon monoxide. We test our method against high level ab initio calculations for a simple model system of myoglobin's heme pocket. Finally, we discuss our results and compare with previous calculations in the literature.

The kinetics of forming and breaking water−water hydrogen bonds in neat water, an aqueous solution of ethane, and an aqueous solution of NaCl are studied by molecular dynamics simulations. We compare nonpolarizable and polarizable water models to elucidate the effect of water's polarizability on hydrogen bonds. We find that polarizability strengthens the hydrogen bonds and increases the hydrogen bond relaxation time by a factor of between 50% and 100%. The Gibbs energy of activation for breaking hydrogen bonds is ~0.2 kcal·mol^-1 higher for the polarizable water model. Polarizability also causes the rate of forming and breaking hydrogen bonds to be more dependent on the local environment.

Analysis of a series of molecular dynamics simulations reveals that the kinetics of breaking and forming water−water hydrogen bonds is slower in the first solvation shell of a 16-residue polypeptide than in bulk water. The correlation time of hydrogen bonds persists significantly longer near hydrophobic groups than in bulk water. Hydrogen bonds are found to be stronger in the solvation shell of nonpolar groups. We show that the difference in hydrogen-bond kinetics in the different environments can be understood in terms of the energetics and the concerted forming and breaking of hydrogen bonds.

A method for calculating the quantum canonical rate constant of chemical reactions in a many body system by means of a short-time flux autocorrelation function combined with a maximum entropy numerical analytic continuation scheme is presented. The rate constant is expressed as the time integral of the real-time flux autocorrelation function. The real-time flux autocorrelation function is evaluated for short times fully quantum mechanically by path integral Monte Carlo simulations. The maximum entropy approach is then used to extract the rate from the short real-time flux autocorrelation data. We present two numerical tests, one for proton transfer in harmonic dissipative environments in the deep tunneling regime and the other for the two-level model of primary charge separation in the photosynthetic reaction center. The results obtained using the flux autocorrelation data up to the time of no more than βℏ are in excellent agreement with the exact quantum calculation over a wide range of parameters including even the tunneling regime.

A renormalization approach is introduced in quantum thermal annealing. This new global optimization algorithm (QTAR) is applied to a highly frustrated BLN model protein with 46 residues. The underlying quantum sampling algorithms utilized are primitive and staging path integral Monte Carlo. The current method enables us to achieve significant improvement in the success rate for locating the global minimum of this protein, while using much less computational effort, compared to previous schemes used. Further applications and possible enhancements of the algorithm are also discussed.

We investigate a new method (QTA-PIMC) for global optimization on complex potential energy surfaces which combines the path integral Monte Carlo method with quantum and thermal annealing. This method is applied to the BLN protein model (Honeycutt, J. D.; Thirumalai, D. Biopolymers 1992, 32, 695). We show that this new approach outperforms simulated (thermal) annealing (SA) and that in fact SA is a subset of our method. This means that we could invoke the effects of both quantum and/or thermal annealing in the global optimization process, hence the name quantum thermal annealing (QTA-PIMC). The simulation results also suggest that QTA-PIMC scales better than SA in terms of system size in the search for the global minimum.

Molecular dynamics simulations of hydrated chloride ions have been performed with a polarizable model for interface geometries of varying curvature, ranging from clusters to planar surfaces. The solvation depth profile of the chloride ion is found to depend dramatically on the curvature of the interface. This behavior is consistent with the structure-breaking character of the chloride ion, and is successfully analyzed in terms of a simple geometric model. This model is expected to be useful in predicting analogous behavior in other ionic species.

We present a study of the classical limit of nonradiative electronic relaxation in condensed phase systems. The discrete Hamiltonian representing an impurity in a condensed phase environment is mapped onto a continuous form using the Meyer−Miller approach. The classical electronic relaxation rate is obtained within the framework of the reactive flux formalism and is compared to the fully quantum mechanical result, and to a mixed quantum−classical approximation. Similar to the case of vibrational relaxation, we find that the fully classical treatment is closer to the fully quantum mechanical rate than the mixed quantum−classical treatment. We provide a time domain analysis of the results.

A detailed study of mixed quantum-classical approximations for radiative and nonradiative processes in condensed phase systems is presented and each approximation is compared to exact fully quantum mechanical dynamics. The problems are formulated in terms of a quantum mechanical time correlation function, and the corresponding mixed quantum-classical descriptions are obtained following the general methodology of Wigner−Kirkwood based on the expansion in powers of Planck's constant. Illustrative examples of the performance and applicability of mixed quantum-classical treatments include vibrational and electronic energy relaxation processes, and the calculation of vibronic absorption spectrum.

We performed studies of fluctuating charge, fluctuating dipole, and combined models for substituted benzenes and concluded that dipoles are necessary to avoid errors in important cases. Force fields incorporating fluctuating dipoles for alanine, serine, and phenylalanine were developed that accurately reproduce both relative conformational energies and cooperative many-body energies as given by ab initio quantum chemical calculations. The polarization model was fit to quantum chemical calculations of changes in the electrostatic potential (ESP) induced by applied perturbations. The electrostatic model was completed by adding fixed charges fit to the zero-field quantum chemical ESP. All intramolecular and Lennard−Jones parameters, and some torsional parameters, were taken from the OPLS-AA force field of Jorgensen and co-workers. Key torsional parameters were refit to quantum chemical structures and energies.

The structural and thermodynamic properties of water are studied using the force bias Monte Carlo simulation. In particular for ST2 water, the effect of system size is examined with 27, 125 and 216 water molecules. The role played by the truncation of the intermolecular potential is analysed using two different truncations, the spherical cut-off and the cubic cut-off. Also a recent simulation with the Watts potential using Ewald summation by McDonald and Klein is compared with one employing the spherical cut-off. In all cases the angular correlation functions show a strong dependence on the type of boundary condition used, whereas the usual radial functions goo(r), goh(r) and ghh(r) do not depend much on the boundary conditions. Because of this dependence of angular correlations on the boundary conditions, care must be exercised in comparing simulation results from small systems to real experiments.

The long-chained fatty acids, which are precursors of prostaglandins and leukotrienes, were examined in plasma lipid esters and adipose tissue obtained from 20 male psoriatic patients and 36 matched controls. The fatty-acid composition of the plasma lipid esters (cholesterol esters, triglycerides and phospholipids) and adipose tissue was assayed using thin-layer and gas chromatography. In comparison with healthy controls, the patients' plasma lipid esters contained significantly lower levels of linoleic acid (18:2 ?6) and a-linolenic acid (18:3 ?3), and higher levels of dihomo-?-linolenic acid (20:3 ?6). In the adipose tissue of the patients, the amount of a-linolenic acid was significantly decreased, while that of arachidonic acid (20:4 ?6) was increased. The observed changes were more pronounced in patients with severe psoriasis than in those with a milder form of the disease. Our results suggest that psoriatic patients differ from healthy controls with regard to the distribution of several of the essential long-chained fatty acids involved in the biosynthesis of prostaglandins and leukotrienes. The relevance of these findings to the development of psoriasis remains to be established.

UV‐induced DNA damage appears to play an essential role in skin car‐cinogenesis. Following acute UV irradiation, there is an overexpression of normal p53 protein in epidermal keratinocytes, representing a physiological response to DNA damage. Sun protection through topical sunscreens or clothing is believed to reduce the hazardous effects of UV irradiation and subsequently the risk of skin cancer. We have examined the effect of an SPF 15 topical sunscreen and blue denim fabric (SPF 1700) in chronically sun‐exposed human skin after sun exposure during a normal summer. Skin biopsies from sun‐protected and sun‐exposed skin were compared with respect to immunohistochemically detectable p53. This method provides a model for assessing the significance of different degrees of UV protection under physiological conditions. Our results show a significant reduction of p53‐positive cells in sun‐protected skin as compared with sun‐exposed skin. The reduction of p53‐positive keratinocytes differed between topical sunscreen (33% reduction) and blue denim fabric (66% reduction). Interindividual variations were large, possibly because of variations in sun exposure. These variations also suggest that mechanisms determining UV damage at the cellular level are complex. The role of residual p53‐positive keratinocytes after 2 months of total sun‐protection (i.e., SPF 1700) is discussed.

The free energy of formation of a droplet in a finite system containingN particles in a box of volumeV at a temperatureT is examined. For certain values of the supersaturation the free energy of formation has a maximum and a minimum. The maximum gives rise to a barrier to nucleation whereas the minimum corresponds to the formation of a stable droplet in equilibrium with vapor. Vapor imperfection and the radius dependence of the surface tension of the droplet are shown to affect the barrier and associated cluster distributions at equilibrium in significant ways. The theory is compared with computer simulation results using a Lennard-Jones fluid at a temperature of 84 K.

An optimized version of the force bias scheme is presented for the Monte Carlo simulation of water in which the random walk of the individual molecule is biased in the direction of the force and torque acting on the molecule. A new criterion is developed to judge the efficiency of sampling the configuration space by studying the translational and rotational diffusion of individual molecules during the random walk. The force bias method is compared with the uniform sampling method using ST2 water as an example, and with molecular dynamics. Similarities and differences between molecular dynamics and Monte Carlo are discussed with respect to pair correlations and energy distributions.

Abstract: The antimalarial drug chloroquine has a high affinity for melanin and accumulates in melanin-rich compartments such as those of the eye. Chloroquine is also deposited in cutaneous tissue, but whether the drug distribution is restricted to melanin-producing cells of the skin is not known. In the present study, the uptake of chloroquine by normal human epidermal keratinocytes was compared with that by melanocytes. Selectively cultivated cells were incubated at drug concentrations ranging between 0 and 10 000 ng/ml for periods of up to 48 h. Chloroquine was quantified in cells and medium using high performance liquid chromatography and fluorometric detection. In both types of cells there was a rapid uptake of chloroquine within the first 2 h, followed by a slower uptake for 2–6 h until a steady-state condition was reached. Dose dependency was linear, with no sign of saturation, and approximately ten times higher drug concentrations were attained in melanocytes as compared with keratinocytes. No formation of desethylchloroquine, the major systemic metabolite, was detected in either cell type. The observed affinity of chloroquine for normal epidermal melanocytes in vitro suggests that the density and melanogenic activity of skin pigment cells may influence the cutaneous drug disposition of chloroquine.

An efficient integration scheme is proposed based on the reversible reference system propagator algorithm (r-RESPA) for the molecular dynamics simulation of molecular solids or liquids at constant pressure. Starting from the Parrinello-Rhaman Lagrangian, the algorithm has been obtained using a Trotter factorization for the classical propagator. This r-RESPA scheme allows us to simulate efficiently the dynamics of completely flexible molecules in the condensed phases, under the constraint of constant pressure. The method may find potential application in the study of mesophases such as nematic or plastic crystals, or in studying the effect of pressure on the spectral properties of solids.

Vitamin A and its derivatives (retinoids) exert modulatory effects on epithelial differentiation and are used therapeutically against skin cancers, but the role of dietary vitamin A in ultraviolet (UV)-induced carcinogenesis is far from clear. To study this process, 220 hairless mice were given diets containing low (0.3-0.6 mg/kg; A-) or high (4-6 mg/kg; A+) amounts of retinol, which resulted after 2 months in an 4-fold difference in liver and skin vitamin A levels as determined by HPLC. Commencing after 1 month of diet, daily irradiations with UVB (280-320 nm) or UVAB (280-380 nm) were given to 176 of the animals for 18 weeks (cumulative doses of UVB and UVA: 26 J/cm² and 168 J/cm², respectively). The first skin tumours, known to be squamous cell carcinomas, appeared after 35 weeks in the UVAB-irradiated A+ animals and 5-6 weeks later in the other groups. After one year the frequency of tumour-bearing animals was 49-63% in the A+ groups and 28-39% in the A- groups (P = 0.003). Two months later the corresponding figures were 66-72% and 50-53%, respectively (P = 0.014). Disregarding the effect of dietary vitamin A, there was no difference in the final tumour incidence between UVB- and UVAB-irradiated animals. The epidermal vitamin A content at 72 h post-irradiation was 60% lower in A+ animals and 10% lower in A- animals compared with the non-irradiated controls. Rather then protecting against skin cancer, a diet rich in vitamin A seems to facilitate UV carcinogenesis in hairless mice. A possible explanation is that photo-decomposition of excessive vitamin A generates short-lived intermediates that may act as photosensitizers during cutaneous carcinogenesis.

Abstract: Path-integral Monte Carlo simulations are used to investigate the possibility of binding of an excess electron to water clusters. Model potentials are used to characterize the interaction between the excess electron and a water monomer and between two water molecules. The simulations reveal that two water molecules can bind an electron. In addition, it is found that the excess electron can be trapped in the field of three water molecules arranged in a linear configuration. The results are used to comment on recent molecular beam experiments.