Computational investigation of molecular mechanism and neuropathological implications in Huntington disease.

Huntington's disorder (HD), caused by mutations of the IT-15 gene, is an autosomal genetic disease that causes the breakdown of the nerve cells in the brain. The IT-15 gene encodes the huntingtin (Htt) protein. Htt, along with its interacting partners, are involved in maintaining proper communication among neurons. Our work is based on the interaction behavior between Htt (in three polyglutamine (polyQ) states that is Htt 0Q, 17Q and 36Q) and SH3GL3 interacting protein by using computational methods. We used the HADDOCK docking platform to find out the extent of interaction between Htt polyQ models and SH3GL3. The Htt36Q (mutated) showed higher interaction than Htt17Q (native) with SH3GL3. Molecular dynamics simulation was performed to uncover the structural fluctuations of polyQ models and their complexes. RMSD, Rg, SASA, and total interaction energy graph showed significant results, where as mutant Htt showed higher fluctuations and flexibility than native Htt. The increase in the length of polyQ was found to affect the stability, flexibility, and compactness of the protein and its complex. Our research provided a propitious approach to understand the consequence of polyglutamination in Htt and its relation with HD.

Biophysical Aspect of Huntingtin Protein During polyQ: An In Silico Insight.

Huntington's disease (HD) is a neurodegenerative disorder that is caused by an abnormal elongation of the polyglutamine (polyQ) chain in the Huntington (Htt) protein. At present, the normal function of Htt of neurons as well as the mechanism by which selective neurodegeneration is caused by the expanded polyQ chain in Htt remains ambiguous. A gain of function as a result of the elongated polyQ chain can lead to abnormal interaction of the Htt protein with its interacting partners, thereby resulting in the neuropathological changes seen in the Huntington's disease. Recent research indicates protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1) as one of the interacting partners of Htt protein. It has proven experimentally that the mutant Htt and PACSIN1 formed aggregates in the cytoplasm. This aggregation is believed to be a cause for Huntington's disease. In our study, we performed in silico investigations to predict the biomolecular mechanism of Htt/PACSIN1 interaction that could be one of the major triggers of the disease. Biomolecular interaction and molecular dynamics simulation analysis were performed to understand the dynamic behavior of native and mutant structures at the atomic level. Mutant Htt showed more interaction with its biological partner than the native Htt due to its expansion of interaction surface and flexible nature of binding residues. Our investigation of native and mutant Htt clearly shows that the structural and functional consequences of the polyQ elongation cause HD. Because of the central role of the Htt-PACSIN1 complex in maintaining connections between neurons, these differences likely contribute to the mechanism responsible for HD progression.