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Many of the molecular mechanisms underlying the pathological aggregation ofproteins observed in neurodegenerative diseases are still not fully understood.Among the diseases associated with protein aggregates, for example, AmyotrophicLateral Sclerosis (ALS) is of relevant importance. Although understanding theprocesses that cause the disease is still an open challenge, its relationshipwith protein aggregation is widely known. In particular, human TDP-43, anRNA/DNA binding protein, is a major component of pathological cytoplasmicinclusions described in ALS patients. The deposition of the phosphorylatedfull-length TDP-43 in spinal cord cells has been widely studied, and it hasbeen shown that the brain cortex presents an accumulation of phosphorylatedC-terminal fragments (CTFs). Even if it is debated whether CTFs represent aprimary cause of ALS, they are a hallmark of TDP-43 related neurodegenerationin the brain. Here, we investigate the CTFs aggregation process, providing apossible computational model of interaction based on the evaluation of shapecomplementarity at the interfaces. To this end, extensive Molecular Dynamics(MD) simulations were conducted for different types of fragments with the aimof exploring the equilibrium configurations. Adopting a newly developedapproach based on Zernike polynomials, for finding complementary regions of themolecular surface, we sampled a large set of exposed portions of the molecularsurface of CTFs structures as obtained from MD simulations. The analysisproposes a set of possible associations between the CTFs, which could drive theaggregation process of the CTFs.

A computational approach to investigate TDP-43 C-terminal fragments aggregation in Amyotrophic Lateral Sclerosis