Nanotech 2010

3D-RISM-KH approach for biomolecular modeling at nanoscale: Thermodynamics of fibril formation and beyond

N. Blinov, L. Dorosh, D. Wishart, A. Kovalenko
University of Alberta/National Institute for Nanotechnology, CA

Keywords: biomolecular simulations, solvation effects, amyloid fibrils, computer-assisted drug design

Abstract:

As an alternative to the conventional solvation models, we propose to use the three-dimensional molecular theory of solvation (3D-RISM-KH approach) as an essential part of a multiscale approach for nanomedical applications. Based on the rigorous statistical-mechanical foundation, this method provides a natural link between different levels of coarse-graining details in the multiscale description of the solvation structure and thermodynamics, from highly localized structural solvent and bound ligand molecules to effective desolvation potentials and self-assembling nanoarchitectures. We apply the 3D-RISM-KH approach to study all stages of formation of fibrillous aggregates and amyloid fibrils. The fibrils are a hallmark of many neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. The formation of amyloid fibrils is a particular example of self-assembly of macromolecules, and as such is governed by general principles of self-assembly. We also show that the 3D-RISM-KH approach is capable of predicting binding sites for the inhibitors of the pathological conversion and aggregation of prion proteins. Using this novel approach for fragment based drug design, we identified the binding modes for this system and demonstrated that the location of the most probable modes are in full agreement with the experimental data.
 
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