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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.