Rational surface design for molecular dynamics simulations of porous polymer adsorbent media

The construction and use of nonflat agarose surfaces in a simulation box, together with the employment of criteria for the immobilization of a set of dextran polymer chains on the nonflat agarose surfaces whose mathematical physics is compatible with that of the criteria used for the immobilization of the same set of dextran polymer chains on flat agarose surfaces, are shown to generate, through the use of molecular dynamics simulations whose simulation box has linear dimensions along the lateral directions that are the same when flat and nonflat agarose surfaces are used, dextran porous polymer structures whose pore sizes at the outermost surface and in the vicinity of the outermost surface of the porous medium can be controlled by an indirect manner through the variation of the parameters that characterize the nonflat surface. The use of a nonflat surface for the generation of desired large pores requires only a small or modest increase in the number of solvent molecules in the simulation box, while the use of a flat surface for the construction of the same desired large pores requires significant increases in the size of the linear dimensions of the flat surface. This increases so substantially the number of solvent molecules that the computational loads become intractable. The results in this work show that through the use of nonflat surfaces porous dextran polymer layers having pores of desired sizes can be effectively constructed, and this approach could be used for the design and construction of polymer-based porous adsorbent media that could effectively facilitate the transport and adsorption of an adsorbate biomolecule of interest that must be separated from a mixture of components. A useful definition about the properties that a porous polymer structure must have in order to become, for an adsorbate biomolecule of interest of known molecular size, a useful adsorbent medium, is presented and is used to (1) evaluate the porous polymer structures generated through the employment of different nonflat surface models and (2) determine and select the nonflat surface model from a set of nonflat surface models that is effective in producing promising porous structures. Then a procedure is presented by which a set of porous polymer media is generated through the use of the selected nonflat surface model, and the desired porous structure from this set is determined and could be considered to be used for the transport and immobilization of the selected affinity groups/ligands and the subsequent transport and adsorption of the desired to be separated adsorbate.     

Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphosphoryl-β-D-ribofuranose 2'-oxidase DprE1

Benzothiazinones (BTZs) are antituberculosis drug candidates with nanomolar bactericidal activity against tubercle bacilli. Here we demonstrate that BTZs are suicide substrates of the FAD-dependent decaprenylphosphoryl-β-D-ribofuranose 2'-oxidase DprE1, an enzyme involved in cell-wall biogenesis. BTZs are reduced by DprE1 to an electrophile, which then reacts in a near-quantitative manner with an active-site cysteine of DprE1, thus providing a rationale for the extraordinary potency of BTZs. Mutant DprE1 enzymes from BTZ-resistant strains reduce BTZs to inert metabolites while avoiding covalent inactivation. Our results explain the basis for drug sensitivity and resistance to an exceptionally potent class of antituberculosis agents.     

On nonlinear ill-posed inverse problems with applications to pricing of defaultable bonds and option pricing

This paper considers the estimation of an unknown function h that can be characterized as a solution to a nonlinear operator equation mapping between two infinite dimensional Hilbert spaces. The nonlinear operator is unknown but can be consistently estimated, and its inverse is discontinuous, rendering the problem ill-posed. We establish the consistency for the class of estimators that are regularized using general lower semicompact penalty functions. We derive the optimal convergence rates of the estimators under the Hilbert scale norms. We apply our results to two important problems in economics and finance: (1) estimating the parameters of the pricing kernel of defaultable bonds; (2) recovering the volatility surface implied by option prices allowing for measurement error in the option prices and numerical error in the computation of the operator. The first anther was supported by US National Science Foundation (Grant No. SES-0631613) and the Cowles Foundation for Research in Economics     

Directing in Vitro Selection towards G-quadruplex-forming Aptamers to Inhibit HMGB1 Pathological Activity

In the search for novel, effective inhibitors of High-Mobility Group Box1 (HMGB1)—a protein involved in various inflammatory and autoimmune diseases as well as in cancer—we herein discovered a set of anti-HMGB1 G-quadruplex(G4)-forming aptamers by using an in vitro selection procedure applied to a doped library of guanine-rich oligonucleotides. The selected DNA sequences were then studied in a pseudo-physiological buffer mimicking the extracellular medium, where HMGB1 exerts its pathological activity, using spectroscopic, electrophoretic, and chromatographic techniques. All the oligonucleotides proved to fold into monomeric G4s and in some cases also dimeric species, stable at physiological temperature. Remarkably, the protein preferentially recognized the sequences forming dimeric parallel G4 structures, as evidenced by a properly designed chemiluminescent binding assay which also highlighted a good selectivity of these aptamers for HMGB1. Moreover, all aptamers showed anti-HMGB1 activity, inhibiting protein-induced cell migration. The acquired data allowed identifying L12 as the best anti-HMGB1 aptamer, featured by high thermal and enzymatic stability, no toxicity at least up to 5 μM concentration on healthy cells, along with potent anti-HMGB1 activity (IC₅₀ ca. 28 nM) and good binding affinity for the protein, thus indicating it as a very promising lead candidate for in vivo studies.