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Characterization of neurotoxic and neuroprotective factors by using computational methodologies
Responsabile: Luigi Vitagliano, luigi.vitaglianocnr.it
Neurodegenerative diseases are widespread pathologies of large social impact that include: prion, Alzheimer and Parkinson disease, Huntington chorea and amyotrophic lateral sclerosis. The onset of these diseases is commonly associated with the accumulation of insoluble amyloid plaques in specific neuronal population. In this scenario, research activities for the prevention and the treatment of these diseases are focused on two distinct directions: (a) the enhancement of factors that promote the survival and maintenance of nerve cells and (b) the definition of the molecular processes that lead to the onset of neurodegenerative diseases. In this framework, the activities here described are focused on the analysis of structural/dynamic determinants of the function of neuroprotective proteins (neurotrophins) (1, 2) and the study of structural properties of amyloid aggregates and their toxic precursors (3, 8). Computations carried out on neurotrophins have not only provided clues on the intrinsic dynamic features of these proteins, but they have also suggested strategies for the design and the development of new compounds of potential therapeutic interest (1, 2). Furthermore, Molecular dynamics simulations have provided valuable information on the conformational preferences of amyloid-like aggregates in non-crystalline environments. Notably, these investigations are also providing clues on the genesis of oligomeric amyloid-like states and on the structural basis of their toxicity
Figure 1. Model of polyglutamine fibers as derived from molecular dynamics studies.
Figure 2. A 310 helical model of NT4 N-terminal peptide derived from the simulation (cyan) superimposed on the N-terminal region of the NT4 (pink) in the NT4-TrkB complex.
1) Stanzione F, Esposito L, Paladino A, Pedone C, Morelli G, Vitagliano L. Role of the conformational versatility of the neurotrophin N-terminal regions in their recognition by Trk receptors. Biophysical J. 2010, 99: 2273-8. 2) Colangelo AM, Bianco MR, Vitagliano L, Cavaliere C, Cirillo G, De Gioia L, Diana D, Colombo D, Redaelli C, Zaccaro L, Morelli G, Papa M, Sarmientos P, Alberghina L, Martegani E. A new Nerve Growth Factor (NGF)-mimetic peptide active on neuropathic pain in rats. J Neurosci. 2008 28: 2698-7093) Vitagliano L, Stanzione F, De Simone A, Esposito L. Dynamics and stability of amyloid-like steric zipper assemblies with hydrophobic dry interfaces. Biopolymers. 2009 91: 1161-1171. 4) De Simone A, Esposito L, Pedone C, Vitagliano L. Insights into stability and toxicity of amyloid-like oligomers by replica exchange molecular dynamics analyses. Biophys J. 2008 95: 1965-735) Esposito L, Paladino A, Pedone C, Vitagliano L. Insights into structure, stability and toxicity of monomeric and aggregated polyglutamine models from molecular dynamics simulations. Biophys. J. 2008 94: 4031-40. 6) Vitagliano L., Esposito L., Pedone C., De Simone A. Stability of single sheet GNNQQNY aggregates analyzed by replica exchange molecular dynamics: antiparallel versus parallel association. Biochem Biophys Res Commun 2008 377: 1036-41. 7) De Simone A, Pedone C, Vitagliano L. Structure, dynamics and stability of assemblies of the human prion fragment SNQNNF: insights into prion fiber structure. Biochem Biophys Res Commun. 2008 366: 800-6. 8) Esposito, L., Pedone, C. , Vitagliano, L. (2006). Molecular dynamics analyses of cross b-spine steric zipper models: b-sheet twisting and aggregation. Proc. Natl. Acad. Sci. USA 103, 11533-8
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