Thermodynamics of an Intrinsically Disordered Protein by Atomistic Simulations

Abstract

Abeta40, the 40-residue form of Amyloid beta, is an intrinsically disordered protein which is involved in Alzheimer's disease and prone to form fibrils.We explored its conformational landscape by atomistic simulations in explicit solvent and NMR-guided metadynamics, an enhanced sampling technique based on the experimental chemical shifts data that allows predicting the relative free energy of the different states involved in the folding process of a protein.This approach provides a picture in striking consistency with experimental NMR measurements, with the global free energy minimum consisting of non-compact and disordered structures.However, the free energy landscape includes also a large amount of partially folded conformations with a relative high secondary structure content and a free energy only 3 kcal/mol higher than the disordered minimum. This structural characterization of Abeta40 provides a library of possible metastable states which can be involved in the aggregation process and used as targets for docking studies to design inhibitors to bind the Abeta fragments in order to prevent their fibrillation.