The presence of serum tissue transglutaminase and endomysial autoantibodies is predictive of small-bowel abnormalities indicative of celiac disease. There is a good correlation between autoantibody positivity and specific HLA haplotypes. We estimate that the prevalence of celiac disease among Finnish schoolchildren is at least 1 case in 99 children.

The standard approximation in continuum electrostatic theory, that polar liquids respond linearly to changes in electric fields, is examined on a microscopic level by molecular dynamics and thermodynamic perturbation simulations. Electrostatic free energies associated with the process of “charging” a solute in a solvent are evaluated and compared to the predictions from linear response, for a number of compounds. It is found that the linear response approximation generally holds well for monovalent ionic solutes, while it is less accurate for dipolar ones. Deviations observed for dipolar compounds are reflected by unequal curvatures of the free energy functions (potentials of mean force) near their respective minima for the “polar” and “nonpolar states”. The short-range nature of dipolar fields gives relatively larger weight to the innermost solvation shells in determining the electrostatic part of the solvation energy, compared to the case of ionic solutes. These inner shells can exhibit nonlinear response due to saturation and/or disruption of the H-bond network (in protic solvents) near the solute. This nonlinearity appears to reach a maximum when the strengths of solute−solvent and solvent−solvent interactions are matched. We also find that the average potential produced by solvent water is negative for an uncharged van der Waals cavity. While this has no bearing on the validity of linear response, it affects the magnitude of the hydration energy for certain ions. Relationships between solvation energies and average interaction energies, derived in this work, can be useful for simplified free energy calculations and their applications to drug design.

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A recent method for estimating ligand binding affinities is extended. This method employs averages of interaction potential energy terms from molecular dynamics simulations or other thermal conformational sampling techniques. Incorporation of systematic deviations from electrostatic linear response, derived from free energy perturbation studies, into the absolute binding free energy expression significantly enhances the accuracy of the approach. This type of method may be useful for computational prediction of ligand binding strengths, e.g., in drug design applications.

The charge-on-spring method is used to develop a rigid, three-site, polarizable water model, a noniterative and a self-consistent version. In this method, the polarizability is taken into account by a variable separation of charges on selected polarizable centers. One of the pair of polarization charges resides on a polarizable center, while the other one is treated as an additional particle attached to the polarizable center by a parabolic restraint potential. The separation is calculated in response to the instantaneous electric field. We parametrized two models which are based on noniterative and self-consistent versions of the method, respectively. We computed several liquid-phase and gas-phase properties and compared with data available from experiment and ab initio calculations. The condensed-phase properties of both models are in reasonable accord with experiment, apart from discrepancies in electrostatic properties consistent with a slightly too large liquid-state dipole. The charge-on-spring method is used to develop a rigid, three-site, polarizable water model, a noniterative and a self-consistent version. In this method, the polarizability is taken into account by a variable separation of charges on selected polarizable centers. One of the pair of polarization charges resides on a polarizable center, while the other one is treated as an additional particle attached to the polarizable center by a parabolic restraint potential. The separation is calculated in response to the instantaneous electric field. We parametrized two models which are based on noniterative and self-consistent versions of the method, respectively. We computed several liquid-phase and gas-phase properties and compared with data available from experiment and ab initio calculations. The condensed-phase properties of both models are in reasonable accord with experiment, apart from discrepancies in electrostatic properties consistent with a slightly too large liquid-state dipole.

The earliest contact between antigen and the innate immune system is thought to direct the subsequent antigen-specific T cell response. We hypothesized that cells of the innate immune system, such as natural killer (NK) cells, NK1.1+ T cells (NKT cells), and γ/δ T cells, may regulate the development of allergic airway disease. We demonstrate here that depletion of NK1.1+ cells (NK cells and NKT cells) before immunization inhibits pulmonary eosinophil and CD3+ T cell infiltration as well as increased levels of interleukin (IL)-4, IL-5, and IL-12 in bronchoalveolar lavage fluid in a murine model of allergic asthma. Moreover, systemic allergen-specific immunoglobulin (Ig)E and IgG2a levels and the number of IL-4 and interferon γ–producing splenic cells were diminished in mice depleted of NK1.1+ cells before the priming regime. Depletion of NK1.1+ cells during the challenge period only did not influence pulmonary eosinophilic inflammation. CD1d1 mutant mice, deficient in NKT cells but with normal NK cells, developed lung tissue eosinophilia and allergen-specific IgE levels not different from those observed in wild-type mice. Mice deficient in γ/δ T cells showed a mild attenuation of lung tissue eosinophilia in this model. Taken together, these findings suggest a critical role of NK cells, but not of NKT cells, for the development of allergen-induced airway inflammation, and that this effect of NK cells is exerted during the immunization. If translatable to humans, these data suggest that NK cells may be critically important for deciding whether allergic eosinophilic airway disease will develop. These observations are also compatible with a pathogenic role for the increased NK cell activity observed in human asthma.

Absolute binding free energies for three inhibitors of HIV-1 proteinase were estimated from molecular dynamics simulations by a recently reported linear approximation procedure. The results were in fairly good agreement with experimental binding data. Two of the inhibitors were very similar and, for comparison, their relative free energies of binding were also calculated by free energy perturbation methods, giving virtually the same result. Effects of cut-off radii and charge states of the protein model were examined. The effects of pH on binding of one of the inhibitors were predicted.

Ten C2-symmetric cyclic urea and sulfamide derivatives have been synthesized from L-mannonic gamma-lactone and D-mannitol. The results of experimental measurement of their inhibitory potencies against HIV-1 protease were compared to calculated free energies of binding derived from molecular dynamics (MD) simulations. The compounds were selected, firstly, to enable elucidation of the role of stereochemistry for binding affinity (1a-d) and, secondly, to allow evaluation of the effects of variation in the link to the P1 and P1' phenyl groups on affinity (1a and 2-5). Thirdly, compounds with hydrogen bond-accepting or-donating groups attached to the phenyl groups in the P2 and P2' side chains (6 and 7) were selected. Binding free energies were estimated by a linear response method, whose predictive power for estimating binding affinities from MD simulations was demonstrated.