Skin permeability prediction with MD simulation sampling spatial and alchemical reaction coordinates.

A molecular-level understanding of skin permeation may rationalize and streamline product development, and improve quality and control, of transdermal and topical drug delivery systems. It may also facilitate toxicity and safety assessment of cosmetics and skin care products. Here, we present new molecular dynamics simulation approaches that make it possible to efficiently sample the free energy and local diffusion coefficient across the skin's barrier structure to predict skin permeability and the effects of chemical penetration enhancers. In particular, we introduce a new approach to use two-dimensional reaction coordinates in the accelerated weight histogram method, where we combine sampling along spatial coordinates with an alchemical perturbation virtual coordinate. We present predicted properties for 20 permeants, and demonstrate how our approach improves correlation with ex vivo/in vitro skin permeation data. For the compounds included in this study, the obtained log KPexp-calc mean square difference was 0.9 cm2 h-2.

Phase-change switching in 2D via soft interactions.

We present a new type of phase-change behavior relevant for information storage applications, that can be observed in 2D systems with cluster-forming ability. The temperature-based control of the ordering in 2D particle systems depends on the existence of a crystal-to-glass transition. We perform molecular dynamics simulations of models with soft interactions, demonstrating that the crystalline and amorphous structures can be easily tuned by heat pulses. The physical mechanism responsible for this behavior is a self-assembled polydispersity, that depends on the cluster-forming ability of the interactions. Therefore, the range of real materials that can perform such a transition is very wide in nature, ranging from colloidal suspensions to vortex matter. The state of the art in soft matter experimental setups, controlling interactions, polydispersity and dimensionality, makes it a very fertile ground for practical applications.

On the Path to Optimal Alchemistry.

Alchemical free energy calculations have become a standard and widely used tool, in particular for calculating and comparing binding affinities of drugs. Although methods to compute such free energies have improved significantly over the last decades, the choice of path between the end states of interest is usually still the same as two decades ago. We will show that there is a fundamentally arbitrary, implicit choice of parametrization of this path. To address this, the notion of the length of a path or a metric is required. A metric recently introduced in the context of the accelerated weight histogram method also proves to be very useful here. We demonstrate that this metric can not only improve the efficiency of sampling along a given path, but that it can also be used to improve the actual choice of path. For a set of relevant use cases, the combination of these improvements can increase the efficiency of alchemical free energy calculations by up to a factor 16.

Melting of a two-dimensional monodisperse cluster crystal to a cluster liquid.

Monodisperse ensembles of particles that have cluster crystalline phases at low temperatures can model a number of physical systems, such as vortices in type-1.5 superconductors, colloidal suspensions, and cold atoms. In this work, we study a two-dimensional cluster-forming particle system interacting via an ultrasoft potential. We present a simple mean-field characterization of the cluster-crystal ground state, corroborating with Monte Carlo simulations for a wide range of densities. The efficiency of several Monte Carlo algorithms is compared, and the challenges of thermal equilibrium sampling are identified. We demonstrate that the liquid to cluster-crystal phase transition is of first order and occurs in a single step, and the liquid phase is a cluster liquid.

Riemann metric approach to optimal sampling of multidimensional free-energy landscapes.

Exploring the free-energy landscape along reaction coordinates or system parameters λ is central to many studies of high-dimensional model systems in physics, e.g., large molecules or spin glasses. In simulations this usually requires sampling conformational transitions or phase transitions, but efficient sampling is often difficult to attain due to the roughness of the energy landscape. For Boltzmann distributions, crossing rates decrease exponentially with free-energy barrier heights. Thus, exponential acceleration can be achieved in simulations by applying an artificial bias along λ tuned such that a flat target distribution is obtained. A flat distribution is, however, an ambiguous concept unless a proper metric is used and is generally suboptimal. Here we propose a multidimensional Riemann metric, which takes the local diffusion into account, and redefine uniform sampling such that it is invariant under nonlinear coordinate transformations. We use the metric in combination with the accelerated weight histogram method, a free-energy calculation and sampling method, to adaptively optimize sampling toward the target distribution prescribed by the metric. We demonstrate that for complex problems, such as molecular dynamics simulations of DNA base-pair opening, sampling uniformly according to the metric, which can be calculated without significant computational overhead, improves sampling efficiency by 50%-70%.

Spatial and temporal distribution of phase slips in Josephson junction chains.

The Josephson effect, tunnelling of a supercurrent through a thin insulator layer between two superconducting islands, is a phenomena characterized by a spatially distributed phase of the superconducting condensate. In recent years, there has been a growing focus on Josephson junction devices particularly for the applications of quantum metrology and superconducting qubits. In this study, we report the development of Josephson junction circuit formed by serially connecting many Superconducting Quantum Interference Devices, SQUIDs. We present experimental measurements as well as numerical simulations of a phase-slip center, a SQUID with weaker junctions, embedded in a Josephson junction chain. The DC transport properties of the chain are the result of phase slips which we simulate using a classical model that includes linear external damping, terminating impedance, as well as internal nonlinear quasiparticle damping. We find good agreement between the simulated and the experimental current voltage characteristics. The simulations allow us to examine the spatial and temporal distribution of phase-slip events occurring across the chains and also the existence of travelling voltage pulses which reflect at the chain edges.

Virus shapes and buckling transitions in spherical shells.

We show that the icosahedral packings of protein capsomeres proposed by Caspar and Klug for spherical viruses become unstable to faceting for sufficiently large virus size, in analogy with the buckling instability of disclinations in two-dimensional crystals. Our model, based on the nonlinear physics of thin elastic shells, produces excellent one-parameter fits in real space to the full three-dimensional shape of large spherical viruses. The faceted shape depends only on the dimensionless Foppl-von Kármán number gamma=YR(2)/kappa, where Y is the two-dimensional Young's modulus of the protein shell, kappa is its bending rigidity, and R is the mean virus radius. The shape can be parametrized more quantitatively in terms of a spherical harmonic expansion. We also investigate elastic shell theory for extremely large gamma, 10(3)

Improving the efficiency of extended ensemble simulations: the accelerated weight histogram method.

We propose a method for efficient simulations in extended ensembles, useful, e.g., for the study of problems with complex energy landscapes and for free energy calculations. The main difficulty in such simulations is the estimation of the a priori unknown weight parameters needed to produce flat histograms. The method combines several complementary techniques, namely, a Gibbs sampler for the parameter moves, a reweighting procedure to optimize data use, and a Bayesian update allowing for systematic refinement of the free energy estimate. In a certain limit the scheme reduces to the 1/t algorithm of B. E. Belardinelli and V. D. Pereyra [Phys. Rev. E 75, 046701 (2007)]. The performance of the method is studied on the two-dimensional Ising model, where comparison with the exact free energy is possible, and on an Ising spin glass.

Generalized anisotropic scaling theory and the transverse meissner transition.

We consider a depinning transition in vortex systems with columnar disorder and tilted applied magnetic fields. From scaling arguments and Monte Carlo simulations, we find that this transverse Meissner transition is governed by a fixed point which is anisotropic in all three directions. This generalization of conventional anisotropic scaling means that the correlation length in different directions diverges with different rates, and we derive exact results for the anisotropy exponents. We make predictions which can be tested in experiments on superconductors with columnar disorder.

Amorphous vortex glass phase in strongly disordered superconductors.

We introduce a model describing vortices in strongly disordered three-dimensional superconductors. The model focuses on the topological defects, i.e., dislocation lines, in an elastic description of the vortex lattice. The model is studied using Monte Carlo simulations, revealing a glass phase at low temperatures, separated by a continuous phase transition to the high temperature resistive vortex liquid phase. The critical exponents nu approximately 1.3 and eta approximately -0.4 characterizing the transition are obtained from finite size scaling.

Vortex glass transition in a random pinning model.

We study the vortex glass transition in disordered high temperature superconductors using Monte Carlo simulations. We use a random pinning model with strong point-correlated quenched disorder, a net applied magnetic field, long-range vortex interactions, and periodic boundary conditions. From a finite size scaling study of the helicity modulus, the rms current, and the resistivity, we obtain critical exponents at the phase transition. The new exponents differ substantially from those of the gauge glass model, but are close to those of the pure three-dimensional XY model.