The statistical-thermodynamic basis for computation of binding affinities: a critical review

Although the statistical thermodynamics of noncovalent binding has been considered in a number of theoretical papers, few methods of computing binding affinities are derived explicitly from this underlying theory. This has contributed to uncertainty and controversy in certain areas. This article therefore reviews and extends the connections of some important computational methods with the underlying statistical thermodynamics. A derivation of the standard free energy of binding forms the basis of this review. This derivation should be useful in formulating novel computational methods for predicting binding affinities. It also permits several important points to be established. For example, it is found that the double-annihilation method of computing binding energy does not yield the standard free energy of binding, but can be modified to yield this quantity. The derivation also makes it possible to define clearly the changes in translational, rotational, configurational, and solvent entropy upon binding. It is argued that molecular mass has a negligible effect upon the standard free energy of binding for biomolecular systems, and that the cratic entropy defined by Gurney is not a useful concept. In addition, the use of continuum models of the solvent in binding calculations is reviewed, and a formalism is presented for incorporating a limited number of solvent molecules explicitly

Modeling the electrophoresis of lysozyme. II. Inclusion of ion relaxation

In this work, boundary element methods are used to model the electrophoretic mobility of lysozyme over the pH range 2–6. The model treats the protein as a rigid body of arbitrary shape and charge distribution derived from the crystal structure. Extending earlier studies, the present work treats the equilibrium electrostatic potential at the level of the full Poisson-Boltzmann (PB) equation and accounts for ion relaxation. This is achieved by solving simultaneously the Poisson, ion transport, and Navier-Stokes equations by an iterative boundary element procedure. Treating the equilibrium electrostatics at the level of the full rather than the linear PB equation, but leaving relaxation out, does improve agreement between experimental and simulated mobilities, including ion relaxation improves it even more. The effects of nonlinear electrostatics and ion relaxation are greatest at low pH, where the net charge on lysozyme is greatest. In the absence of relaxation, a linear dependence of mobility and average polyion surface potential, (lambda zero)s, is observed, and the mobility is well described by the equation [formula: see text] where epsilon 0 is the dielectric constant of the solvent, and eta is the solvent viscosity. This breaks down, however, when ion relaxation is included and the mobility is less than predicted by the above equation. Whether or not ion relaxation is included, the mobility is found to be fairly insensitive to the charge distribution within the lysozyme model or the internal dielectric constant

Poisson-Boltzmann analysis of the lambda repressor-operator interaction

A theoretical study of the ion atmosphere contribution to the binding free energy of the lambda repressor-operator complex is presented. The finite-difference form of the Poisson-Boltzmann equation was solved to calculate the electrostatic interaction energy of the amino-terminal domain of the lambda repressor with a 9 or 45 base pair oligonucleotide. Calculations were performed at various distances between repressor and operator as well as at different salt concentrations to determine ion atmosphere contributions to the total electrostatic interaction. Details in the distribution of charges on DNA and protein atoms had a strong influence on the calculated total interaction energies. In contrast, the calculated salt contributions are relatively insensitive to changes in the details of the charge distribution. The results indicate that the ion atmosphere contribution favors association at all protein-DNA distances studied. The theoretical number of ions released upon repressor-operator binding appears to be in reasonable agreement with experimental data

Adaptive Finite Element Methods with Inexact Solvers for the Nonlinear Poisson-Boltzmann Equation

In this article we study adaptive finite element methods (AFEM) with inexact solvers for a class of semilinear elliptic interface problems. We are particularly interested in nonlinear problems with discontinuous diffusion coefficients, such as the nonlinear Poisson-Boltzmann equation and its regularizations. The algorithm we study consists of the standard SOLVE-ESTIMATE-MARK-REFINE procedure common to many adaptive finite element algorithms, but where the SOLVE step involves only a full solve on the coarsest level, and the remaining levels involve only single Newton updates to the previous approximate solution. We summarize a recently developed AFEM convergence theory for inexact solvers, and present a sequence of numerical experiments that give evidence that the theory does in fact predict the contraction properties of AFEM with inexact solvers. The various routines used are all designed to maintain a linear-time computational complexity.Comment: Submitted to DD20 Proceeding

Computational Physics on Graphics Processing Units

The use of graphics processing units for scientific computations is an emerging strategy that can significantly speed up various different algorithms. In this review, we discuss advances made in the field of computational physics, focusing on classical molecular dynamics, and on quantum simulations for electronic structure calculations using the density functional theory, wave function techniques, and quantum field theory.Comment: Proceedings of the 11th International Conference, PARA 2012, Helsinki, Finland, June 10-13, 201

Constraining Strong Baryon-Dark Matter Interactions with Primordial Nucleosynthesis and Cosmic Rays

Self-interacting dark matter (SIDM) was introduced by Spergel & Steinhardt to address possible discrepancies between collisionless dark matter simulations and observations on scales of less than 1 Mpc. We examine the case in which dark matter particles not only have strong self-interactions but also have strong interactions with baryons. The presence of such interactions will have direct implications for nuclear and particle astrophysics. Among these are a change in the predicted abundances from big bang nucleosynthesis (BBN) and the flux of gamma-rays produced by the decay of neutral pions which originate in collisions between dark matter and Galactic cosmic rays (CR). From these effects we constrain the strength of the baryon--dark matter interactions through the ratio of baryon - dark matter interaction cross section to dark matter mass, $s$. We find that BBN places a weak upper limit to this ratio $< 10^8 cm^2/g$. CR-SIDM interactions, however, limit the possible DM-baryon cross section to $< 5 \times 10^{-3} cm^2/g$; this rules out an energy-independent interaction, but not one which falls with center-of-mass velocity as $s \propto 1/v$ or steeper.Comment: 17 pages, 2 figures; plain LaTeX. To appear in PR