Alzheimer's disease (AD) is a neurodegenerative disorder that lacks effective treatment options. Anti-amyloid beta (Aβ) antibodies are the leading drug candidates to treat AD, but the results of clinical trials have been disappointing. Introducing rational mutations into anti-Aβ antibodies to increase their effectiveness is a way forward, but the path to take is unclear. In this study, we demonstrate the use of computational fragment-based docking and MMPBSA binding free energy calculations in the analysis of anti-Aβ antibodies for rational drug design efforts. Our fragment-based docking method successfully predicts the emergence of the common EFRH epitope. MD simulations coupled with MMPBSA binding free energy calculations are used to analyze scenarios described in prior studies, and we computationally introduce rational mutations into PFA1 to predict mutations that can improve its binding affinity toward the pE3-Aβ form of Aβ. Two out of our four proposed mutations are predicted to stabilize binding. Our study demonstrates that a computational approach may lead to an improved drug candidate for AD in the future.

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Rats respond to iv LPS with a complex thermoregulatory response, which is represented mostly by fever at a neutral Ta, but mostly by hypothermia at a subneutral Ta. Both the febrile and hypothermic components of this response are mediated by PGs, but the exact mechanism of the fever‐hypothermia switch is unknown. Wistar rats were injected with LPS (10, 100 or 1000 μg/kg iv) at a neutral (30°C) or subneutral (20°C) Ta. At 30°C, the febrile components of the response to each LPS dose were more pronounced; at 20°C, the hypothermic components were predominant. At either Ta, LPS caused a dose‐depended increase in plasma PGs within all five cascades (PGE2, D2, F2á, I2 and TXB2), whether measured by ELISA or LC/MS/MS. Irrespective of the method, we found no difference in the plasma response of any individual PG to any dose of LPS at 30°C vs 20°C. We then studied thermoregulatory responses of rats to iv PGs (0.8 μmol/kg, administered as albumin complexes) at 30 and 20°C. Only PGE2 caused a statistically significant fever, and this response was unaffected by Ta. Several PGs, including E2, D2 and I2, caused hypothermia, and this response was restricted to the subneutral conditions. We conclude that, regardless of Ta, LPS causes the same systemic PG response. The fever‐hypothermia switch involves LPS‐induced PGE2, D2 and I2 causing hypothermia in a subneutral (but not neutral) environment.Support: NS041233, NS064480, 11SDG4880051