FEW: A workflow tool for free energy calculations of ligand binding

In the later stages of drug design projects, accurately predicting relative binding affinities of chemically similar compounds to a biomolecular target is of utmost importance for making decisions based on the ranking of such compounds. So far, the extensive application of binding free energy approaches has been hampered by the complex and time‐consuming setup of such calculations. We introduce the free energy workflow (FEW) tool that facilitates setup and execution of binding free energy calculations with the AMBER suite for multiple ligands. FEW allows performing free energy calculations according to the implicit solvent molecular mechanics (MM‐PB(GB)SA), the linear interaction energy, and the thermodynamic integration approaches. We describe the tool's architecture and functionality and demonstrate in a show case study on Factor Xa inhibitors that the time needed for the preparation and analysis of free energy calculations is considerably reduced with FEW compared to a fully manual procedure. © 2013 Wiley Periodicals, Inc.     

Comparative assessment of computational methods for the determination of solvation free energies in alcohol‐based molecules

The determination of differences in solvation free energies between related drug molecules remains an important challenge in computational drug optimization, when fast and accurate calculation of differences in binding free energy are required. In this study, we have evaluated the performance of five commonly used polarized continuum model (PCM) methodologies in the determination of solvation free energies for 53 typical alcohol and alkane small molecules. In addition, the performance of these PCM methods, of a thermodynamic integration (TI) protocol and of the Poisson–Boltzmann (PB) and generalized Born (GB) methods, were tested in the determination of solvation free energies changes for 28 common alkane‐alcohol transformations, by the substitution of an hydrogen atom for a hydroxyl substituent. The results show that the solvation model D (SMD) performs better among the PCM‐based approaches in estimating solvation free energies for alcohol molecules, and solvation free energy changes for alkane‐alcohol transformations, with an average error below 1 kcal/mol for both quantities. However, for the determination of solvation free energy changes on alkane‐alcohol transformation, PB and TI yielded better results. TI was particularly accurate in the treatment of hydroxyl groups additions to aromatic rings (0.53 kcal/mol), a common transformation when optimizing drug‐binding in computer‐aided drug design. © 2013 Wiley Periodicals, Inc.     

Electrical Properties of a Highly Charged Cylindrical Particle in a Symmetric Electrolyte Solution

Based on the extended Langmuir's method, accurate analytic expressions for the electrical properties of cylindrical colloidal particle in a solution of symmetric electrolyte are derived from the nonlinear cylindrical Poisson-Boltzmann equation. Comparison is made with previous literature results. The present formulae have good agreement with literature values and are quite simple for practical use.     

An Approximate Expression for the Degree of Counterion Binding of Dressed Micelles

A simple formula for calculating the degree of counterion binding of dressed micelles is presented. This approximate expression for the spherical micelle is derived from the extending Langmuir's method in the case of high surface potentials. It works quite well for the estimation of the degree of counterion binding of micelles. The simple form is very convenient for practical use.     

Electrical Properties of Cylindrical Reverse Micelle

In this article, accurate analytic expressions of the surface charge density/surface potential and adsorption excesses for cylindrical reverse micelle in a solution of symmetric electrolyte are derived from the nonlinear cylindrical Poisson–Boltzmann equation. These expressions are in good agreement with numerical values and Van Aken's results for cylindrical reverse micelle with high surface potentials and large κa.     

Interpolating solutions of the Poisson equation in the disk based on Radon projections

We consider an algebraic method for reconstruction of a function satisfying the Poisson equation with a polynomial right-hand side in the unit disk. The given data, besides the right-hand side, is assumed to be in the form of a finite number of values of Radon projections of the unknown function. We first homogenize the problem by finding a polynomial which satisfies the given Poisson equation. This leads to an interpolation problem for a harmonic function, which we solve in the space of harmonic polynomials using a previously established method. For the special case where the Radon projections are taken along chords that form a regular convex polygon, we extend the error estimates from the harmonic case to this Poisson problem. Finally we give some numerical examples.     

Nonlocal diffusion,a Mittag-Leffler function and a two-dimensional Volterra integral equation

In this paper we consider a particular class of two-dimensional singular Volterra integral equations. Firstly we show that these integral equations can indeed arise in practice by considering a diffusion problem with an output flux which is nonlocal in time; this problem is shown to admit an analytic solution in the form of an integral. More crucially, the problem can be re-characterized as an integral equation of this particular class. This example then provides motivation for a more general study: an analytic solution is obtained for the case when the kernel and the forcing function are both unity. This analytic solution, in the form of a series solution, is a variant of the Mittag-Leffler function. As a consequence it is an entire function. A Gronwall lemma is obtained. This then permits a general existence and uniqueness theorem to be proved.     

Nonlinear Schrödinger equation in a semi-strip: Evolution of the Weyl–Titchmarsh function and recovery of the initial condition and rectangular matrix solutions from the boundary conditions

Rectangular matrix solutions of the defocusing nonlinear Schrödinger equation (dNLS) are studied in quarter-plane and semi-strip. Evolution of the corresponding Weyl–Titchmarsh (Weyl) function is described in terms of the initial Weyl function and boundary conditions. In the next step, the initial Weyl function is recovered (for the quarter-plane case) from the long-time asymptotics of the wave function considered at the boundary. Thus, it is shown that the evolution of the Weyl function is uniquely defined by the boundary conditions. Moreover, a procedure to recover solutions of dNLS (uniquely defined by the boundary conditions) is given. In a somewhat different way, the same boundary value problem is also dealt with in a semi-strip (for the case of a quasi-analytic initial condition).     

Existence of pulses in excitable media with nonlocal coupling

We prove the existence of fast traveling pulse solutions in excitable media with non-local coupling. Existence results had been known, until now, in the case of local, diffusive coupling and in the case of a discrete medium, with finite-range, non-local coupling. Our approach replaces methods from geometric singular perturbation theory, that had been crucial in previous existence proofs, by a PDE oriented approach, relying on exponential weights, Fredholm theory, and commutator estimates.