Absolute binding free energies for the SAMPL6 cucurbit[8]uril host-guest challenge via the AMOEBA polarizable force field.

As part of the SAMPL6 host-guest blind challenge, the AMOEBA force field was applied to calculate the absolute binding free energy for a cucurbit[8]uril host complexed with 14 diverse guests, ranging from small, rigid structures to drug molecules. The AMOEBA results from the initial submission prompted an investigation into aspects of the methodology and parameterization employed. Lessons learned from the blind challenge include: a double annihilation scheme (electrostatics and van der Waals) is needed to obtain proper sampling of guest conformations, annihilation of key torsion parameters of the guest are recommended for flexible guests, and a more thorough analysis of torsion parameters is warranted. When put in to practice with the AMOEBA model, the lessons learned improved the MUE from 2.63 to 1.20 kcal/mol and the RMSE from 3.62 to 1.68 kcal/mol, respectively. Overall, the AMOEBA protocol for determining absolute binding free energies benefitted from participation in the SAMPL6 host-guest blind challenge and the results suggest the implementation of the methodology in future host-guest calculations.

Twins discordant for myositis and systemic lupus erythematosus show markedly enriched autoantibodies in the affected twin supporting environmental influences in pathogenesis.

BACKGROUND: Studies of twin pairs discordant for autoimmune conditions provide a unique opportunity to explore contributing factors triggered by complex gene-environment interactions. METHODS: In this cross-sectional study, thirty-one monozygotic or dizygotic twin pairs discordant for myositis or systemic lupus erythematosus (SLE), along with matched healthy controls were evaluated for antibodies against a panel of 21 autoantigens. RESULTS: Autoantibody profiling revealed that 42% of the affected twins showed significant seropositivity against autoantigens in the panel. In many of these affected twins, but none of healthy controls, there were high levels of autoantibodies detected against two or more autoantigens commonly seen in systemic autoimmune diseases including Ro52, Ro60, RNP-70 K and/or RNP-A. In contrast, only 10% (3/31) of the unaffected twins showed seropositivity and these immunoreactivities were against single autoantigens not seen in systemic autoimmune diseases. While no significant differences in autoantibodies were detected between the affected or unaffected twins against thyroid peroxidase, transglutaminase and several cytokines, 23% of the affected twins with myositis showed autoantibodies against the gastric ATPase. Analysis of the monozygotic twins separately also revealed a higher frequencies of autoantibodies in the affected twins compared to the unaffected twins (P = 0.046). Lastly, clinical analysis of both the affected monozygotic and dizygotic twins revealed that the autoantibody seropositive affected twins had a greater global disease activity score compared to seronegative affected twins (P = 0.019). CONCLUSION: The findings of significantly more autoantibodies in the affected twins with myositis and SLE compared to the unaffected twins are consistent with potential non-genetic factors playing a role in autoantibody production and pathogenesis of these autoimmune disorders.