The fold of a protein determines its function and its misfolding can result in loss-of-function defects. In addition, for certain proteins their misfolding can lead to gain-of-function toxicities resulting in… Click to show full abstract
The fold of a protein determines its function and its misfolding can result in loss-of-function defects. In addition, for certain proteins their misfolding can lead to gain-of-function toxicities resulting in protein misfolding diseases such as Alzheimer's, Parkinson's, or the prion diseases. In all of these diseases one or more proteins misfold and aggregate into disease-specific assemblies, often in the form of fibrillar amyloid deposits. Most, if not all, protein misfolding diseases share a fundamental molecular mechanism that governs the misfolding and subsequent aggregation. A wide variety of experimental methods have contributed to our knowledge about misfolded protein aggregates, some of which are briefly described in this review. The misfolding mechanism itself is difficult to investigate, as the necessary timescale and resolution of the misfolding events often lie outside of the observable parameter space. Molecular dynamics simulations fill this gap by virtue of their intrinsic, molecular perspective and the step-by-step iterative process that forms the basis of the simulations. This review focuses on molecular dynamics simulations and how they combine with experimental analyses to provide detailed insights into protein misfolding and the ensuing diseases.
               
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