Biophysical Society Thematic Meeting - October 25-30, 2015

Polymers and Self Assembly: From Biology to Nanomaterials Poster Session I

24-POS Board 24 Molecular Solvation Effects in Formation and Stability of Aβ- oligomers and Optimization of Misfolding Inhibitors from Multiscale Platform Using Molecular Theory of Solvation Andriy Kovalenko 1,2 , Neil Cashman 3 , Nikolay Blinov 2,1 . 1 National Institute for Nanotechnology, Edmonton, AB, Canada, 2 University of Alberta, Edmonton, AB, Canada, 3 University of British Columbia, Vancouver, BC, Canada. In neurodegenerative diseases associated with accumulation of fibrillar proteins, elucidation of the mechanisms of formation, recognition, and inhibition of neurotoxic aggregates by therapeutic agents is important for development of therapies against these diseases. 1,2 Molecular modeling provides a valuable insight into the oligomerization mechanisms and structural characteristics of oligomers and amyloid fibrils, 3 and can be useful for initial selection of drug candidates for further experimental screening and optimization of drugs and conformational antibodies targeting neurotoxic aggregates for efficient delivery. 4 Solvation is a major factor in biomolecular processes, including slow exchange and localization of solvent and ions, protein- ligand recognition, and membrane translocation. Statistical-mechanical, 3D-RISM-KH molecular theory of solvation 5,6 accurately describes solvation effects in protein-ligand recognition protocols. 7,8 In a single formalism, the 3D-RISM-KH theory efficiently accounts for electrostatic and non-polar forces, including hydrogen bonding, hydrophobicity, structural solvation and desolvation in crowded cellular environment. A new multiscale modeling platform for optimization of molecular recognition and translocation of antiprion therapeutic agents is based on the implementations of the 3D-RISM-Dock protocol in AutoDock suite, 8 3D-RISM-KH solvent analysis in the Molecular Operating Environment package, 9 and multi-time-step molecular dynamics steered with 3D-RISM-KH effective solvation forces in the Amber molecular dynamics package. 10,11 We apply the new platform to study molecular recognition at the initial stages of oligomerization of Aβ peptides, structural solvation and desolvation effects on stability of amyloid fibrils, binding modes of antiprion compounds, and optimization of antiprion agents for efficient delivery. 1 Frost;Diamond. Nat.Rev.Neurosci.,2010,11,155-9. 2 Biran;et al. J.Cell Mol.Med.,2009,13,61-6. 3 Straub;Thirumalai. Curr.Opin.Struct.Biol.,2010,20,187-195. 4 Subramaniana;Kitchen. J.Comput.Aid.Mol.Des.,2003,17,643-4. 5 Kovalenko. In: Molecular Theory of Solvation. Hirata,F.(ed.) Kluwer, Dordrecht, 2003, pp.169-275. 6 Kovalenko. Pure Appl.Chem.,2013,85,159-99. 7 Blinov;et al. Molec.Simul,2011,37,718-8.

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