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    Molecular simulations of IDPs: From ensemble generation to IDP interactions leading to disorder-to-order transitions
    (Academic Press Inc Elsevier Science, 2021) Fatafta, Hebah; Samantray, Suman; Sayyed-Ahmad, Abdallah; Weber, Orkide Coşkuner; Strodel, Birgit; N. Uversky, Vladimir
    Intrinsically disordered proteins (IDPs) lack a well-defined three-dimensional structure but do exhibit some dynamical and structural ordering. The structural plasticity of IDPs indicates that entropy-driven motions are crucial for their function. Many IDPs undergo function-related disorder-to-order transitions upon by their interaction with specific binding partners. Approaches that are based on both experimental and theoretical tools enable the biophysical characterization of IDPs. Molecular simulations provide insights into IDP structural ensembles and disorder-to-order transition mechanisms. However, such studies depend strongly on the chosen force field parameters and simulation techniques. In this chapter, we provide an overview of IDP characteristics, review all-atom force fields recently developed for IDPs, and present molecular dynamics-based simulation methods that allow IDP ensemble generation as well as the characterization of disorder-to-order transitions. In particular, we introduce meta-dynamics, replica exchange molecular dynamics simulations, and also kinetic models resulting from Markov State modeling, and provide various examples for the successful application of these simulation methods to IDPs.
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    Öğe
    Transition metal Ion interactions with disordered Amyloid-beta Peptides in the pathogenesis of Alzheimer's disease: insights from computational chemistry studies
    (Amer Chemical Soc, 2019) Strodel, Birgit; Weber, Orkide Coşkuner
    Monomers and oligomers of the amyloid-beta peptide aggregate to form the fibrils found in the brains of Alzheimer's disease patients. These monomers and oligomers are largely disordered and can interact with transition metal ions, affecting the mechanism and kinetics of amyloid-beta aggregation. Due to the disordered nature of amyloid-beta, its rapid aggregation, as well as solvent and paramagnetic effects, experimental studies face challenges in the characterization of transition metal ions bound to amyloid-beta monomers and oligomers. The details of the coordination chemistry between transition metals and amyloid-beta obtained from experiments remain debated. Furthermore, the impact of transition metal ion binding on the monomeric or oligomeric amyloid-beta structures and dynamics are still poorly understood. Computational chemistry studies can serve as an important complement to experimental studies and can provide additional knowledge on the binding between amyloid-beta and transition metal ions. Many research groups conducted first-principles calculations, ab initio molecular dynamics simulations, quantum mechanics/classical mechanics simulations, and classical molecular dynamics simulations for studying the interplay between transition metal ions and amyloid-beta monomers and oligomers. This review summarizes the current understanding of transition metal interactions with amyloid-beta obtained from computational chemistry studies. We also emphasize the current view of the coordination chemistry between transition metal ions and amyloid-beta. This information represents an important foundation for future metal ion chelator and drug design studies aiming to combat Alzheimer's disease.