Novel Allosteric Sites on Ras for Lead Generation

Aberrant Ras activity is a hallmark of diverse cancers and developmental diseases. Unfortunately, conventional efforts to develop effective small molecule Ras inhibitors have met with limited success. We have developed a novel multi-level computational approach to discover potential inhibitors of previously uncharacterized allosteric sites. Our approach couples bioinformatics analysis, advanced molecular simulations, ensemble docking and initial experimental testing of potential inhibitors. Molecular dynamics simulation highlighted conserved allosteric coupling of the nucleotide-binding switch region with distal regions, including loop 7 and helix 5. Bioinformatics methods identified novel transient small molecule binding pockets close to these regions and in the vicinity of the conformationally responsive switch region. Candidate binders for these pockets were selected through ensemble docking of ZINC and NCI compound libraries. Finally, cell-based assays confirmed our hypothesis that the chosen binders can inhibit the downstream signaling activity of Ras. We thus propose that the predicted allosteric sites are viable targets for the development and optimization of new drugs

Convergence Analysis of Triangular MAC Schemes for Two Dimensional Stokes Equations

In this paper, we consider the use of H(div) elements in the velocity?Cpressure formulation to discretize Stokes equations in two dimensions. We address the error estimate of the element pair (Formula Presented.), which is known to be suboptimal, and render the error estimate optimal by the symmetry of the grids and by the superconvergence result of Lagrange interpolant. By enlarging (Formula Presented.) such that it becomes a modified $$\mathrm{BDM}$$BDM-type element, we develop a new discretization (Formula Presented.). We, therefore, generalize the classical MAC scheme on rectangular grids to triangular grids and retain all the desirable properties of the MAC scheme: exact divergence-free, solver-friendly, and local conservation of physical quantities. Further, we prove that the proposed discretization (Formula Presented.) achieves the optimal convergence rate for both velocity and pressure on general quasi-uniform grids, and one and half order convergence rate for the vorticity and a recovered pressure. We demonstrate the validity of theories developed here by numerical experiments. ? 2014, Springer Science+Business Media New York.SCI(E)[email protected]; [email protected]; [email protected]

Mimetic spectral element method for anisotropic diffusion

This paper addresses the topological structure of steady, anisotropic, inhomogeneous diffusion problems. Two discrete formulations: a) mixed and b) direct formulations are discussed. Differential operators are represented by sparse incidence matrices, while weighted mass matrices play the role of metric-dependent Hodge matrices. The resulting mixed formulations are point-wise divergence-free if the right hand side function f = 0. The method is inf-sup stable and displays optimal convergence on orthogonal and non-affine grids.Comment: 43 page