EVENTO ANNULLATO

Enhanced Sampling to Investigate Protein Folding Dynamics and Kinetics in Neurodegenerative Rare Diseases with focus on Spinocerebellar Ataxia

Proteins are fascinating molecular machines capable of organizing themselves into well-defined hierarchical structures through a huge number of conformational changes to accomplish a wide range of cellular functions. Moreover, the alternative protein conformations may enable the exposition of hydrophobic protein domains, increasing aberrant aggregation risk. This is the case of amyloidogenic proteins, where a direct correlation between thermodynamic stability and the propensity for amyloid fibril formation is widely demonstrated. As a consequence, determining protein dynamics, folding kinetics and thermodynamics represents a significant scientific challenge for both experimental and computational approaches to date. Molecular modeling may play a key role in describing protein tendencies towards specific conformational rearrangements and protein-protein organization. Approaching this problem from an energetic point of view is of great importance especially in case of amyloidogenic proteins, given the intimate interconnection between the functional energy landscape and aggregation risk. In this connection, new insight by enhanced sampling molecular dynamics simulations on conformational dynamics and kinetics of the AXH monomer of Ataxin-1 and the Josephin Domain of Ataxin 3 will be presented. Both proteins play a crucial role in aggregation and fibrillogenesis characterizing two rare amyloidogenic diseases, Spinocerebellar ataxia type 1 and 3, respectively. In a greater detail, approaches such as classical molecular dynamics, metadynamics guided by principal components of the protein motion, replica exchange molecular dynamics, functional mode analysis have been employed to provide an quantitative estimation of the free energy landscape characterizing the transition pathway among several molecular arrangements of these proteins and to characterize the dimerization dynamics and kinetics.