CDOCKER and $$\lambda$$-dynamics for prospective prediction in D3R Grand Challenge 2

The opportunity to prospectively predict ligand bound poses and free energies of binding to the Farnesoid X Receptor in the D3R Grand Challenge 2 provided a useful exercise to evaluate CHARMM based docking (CDOCKER) and \(\lambda\)-dynamics methodologies for use in “real-world” applications in computer aided drug design. In addition to measuring their current performance, several recent methodological developments have been analyzed retrospectively to highlight best procedural practices in future applications. For pose prediction with CDOCKER, when the protein structure used for rigid receptor docking was close to the crystallographic holo structure, reliable poses were obtained. Benzimidazoles, with a known holo receptor structure, were successfully docked with an average RMSD of 0.97 \(\AA\). Other non-benzimidazole ligands displayed less accuracy largely because the receptor structures we chose for docking were too different from the experimental holo structures. However, retrospective analysis has shown that when these ligands were re-docked into their holo structures, the average RMSD dropped to 1.18 \(\AA\) for all ligands. When sulfonamides and spiros were docked with the apo structure, which agrees more with their holo structure than the structures we chose, five out of six ligands were correctly docked. These docking results emphasize the need for flexible receptor docking approaches. For \(\lambda\)-dynamics techniques, including multisite \(\lambda\)-dynamics (MS\(\lambda\)D), reasonable agreement with experiment was observed for the 33 ligands investigated; root mean square errors of 2.08 and 1.67 kcal/mol were obtained for free energy sets 1 and 2, respectively. Retrospectively, soft-core potentials, adaptive landscape flattening, and biasing potential replica exchange (BP-REX) algorithms were critical to model large substituent perturbations with sufficient precision and within restrictive timeframes, such as was required with participation in Grand Challenge 2. These developments, their associated benefits, and proposed procedures for their use in future applications are discussed.     

Effective pair potentials in fluids in the presence of three-body forces

The physical properties of a fluid in which there is only a two-body potential, u_αβ , can be expressed in terms of the total correlation function, h ₁₂, which is a sum of all connected graphs with root-points on molecules 1 and 2, whose links are f bonds, where f_αβ = exp (-u_αβ/κT) - 1. It is shown that the total correlation function in the presence of a weak three-body potential, u_αβγ , is h ₁₂*, where h ₁₂* is the sum of all two-body connected graphs in which each f bond is replaced in turn by an f* bond, where

and where ? is a sub-set of the elementary graphs each of which contains one f_αβγ link. We call this sub-set the line-irreducible graphs, and its leading term is a graph discussed by Rushbrooke and Silbert.

The three-body potential is set equal to the dipole-dipole-dipole potential of Axilrod and Teller, and the analytic properties and numerical values of the first term ?₁ examined in detail.

Other effective potentials have been defined and the relations between them are elucidated. In particular it is shown that the first term in ? cannot be used to obtain the effective link f* at liquid densities, but that it can be compared with the dependence on density of the effective potential u* obtained by Mikolaj and Pings from the x-ray diffraction of compressed argon.     

Intense slow positron production at the 15 MeV LINAC at Argonne National Laboratory

An intense slow positron beam using a 15 MeV LINAC (average current 1.25 × 10¹⁵ e⁻/s) at the Radiation and Photochemistry Group, Chemistry Division of Argonne National Laboratory (ANL) has been proposed and studied. Computer simulated results optimizing the positron yield and distribution of energy and angle show that a slow positron production at 10¹⁰ e⁺/s is possible. A proposed design of an intense slow positron beam with optimal conditions of incident electron, converter/moderator configurations, and extraction/transportation is presented.     

Flow phenomena in floppy tubes

Collapsible tubes, which occur all over the body, have unique properties from the point of view of both physics and physiology. A brief review is attempted of first the basic observable properties, followed by simple theory to explain the steady-flow aspects and an overview of the somewhat more complex theories for unsteady flow, in particular the flow-induced oscillations. The experimental evidence from laboratory studies is reviewed with particular emphasis on the dynamical system aspects. A final section looks at the current position and prospects.     

Magnetism and superconductivity in ErNi2B2C

We have performed a series of neutron diffraction experiments from the magnetic order and the vortex lattice in single crystal ErNi₂B₂C. The incommensurate magnetic structure develops additional even harmonics below the ‘ferromagnetic’ ordering temperature, T _F of 2.3 K. This feature and the existence of rods of diffuse scattering suggest the development of ferromagnetic microdomain walls. The magnetic structure is very sensitive to the application of a magnetic field with changes in modulation vector and harmonic content. Studies of the vortex lattice show the presence of a 45° reorientation transition and a distorted hexagonal to square transition as a function of applied field. Further distortions of the vortex lattice occur at T _N, but no changes are seen at T _F.     

Development of the Argonne positron source APosS

In this paper we discuss the progress at Argonne National Laboratory with the APosS. We outline possible improvements that can increase the flux of positrons by increasing the electron current on target or by modification of the positron converter. We discuss some new techniques that could increase moderation efficiency and thus further increase positron flux two to three orders of magnitude by making use of modern accelerator techniques.