title: Computational investigation of molecular mechanism and neuropathological implications in Huntington disease.
abstract: 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.
authors.affiliation: School of Bio Sciences and Technology (SBST), Bioinformatics Division Vellore Institute of Technology University, Vellore, 632014, Tamil Nadu, India.
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Gopalakrishnan
authors.affiliation: School of Bio Sciences and Technology (SBST), Bioinformatics Division Vellore Institute of Technology University, Vellore, 632014, Tamil Nadu, India.
authors.forename: Namrata
authors.initials: N
authors.lastname: Kalsi
authors.affiliation: School of Bio Sciences and Technology (SBST), Bioinformatics Division Vellore Institute of Technology University, Vellore, 632014, Tamil Nadu, India.
authors.forename: Shraddha
authors.initials: S
authors.lastname: Jethi
authors.affiliation: Division of Biotechnology, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India. riturajpurohit@gmail.com.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Purohit
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D019295:Computational Biology / Q000379:methods*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000473:pathology; D010455:Peptides / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; C115574:SH3GL3 protein, human; C097188:polyglutamine
keywords: Biological partner; Huntingtin; Molecular dynamics; Polyglutamine