In this work, the most detrimental missense mutations of aspartoacylase that cause Canavan's disease were identified computationally and the substrate binding efficiencies of those missense mutations were analyzed. Out of 30 missense mutations, I-Mutant 2.0, SIFT and PolyPhen programs identified 22 variants that were less stable, deleterious and damaging respectively. Subsequently, modeling of these 22 variants was performed to understand the change in their conformations with respect to the native aspartoacylase by computing their root mean squared deviation (RMSD). Furthermore, the native protein and the 22 mutants were docked with the substrate NAA (N-Acetyl-Aspartic acid) to explain the substrate binding efficiencies of those detrimental missense mutations. Among the 22 mutants, the docking studies identified that 15 mutants caused lower binding affinity for NAA than the native protein. Finally, normal mode analysis determined that the loss of binding affinity of these 15 mutants was caused by altered flexibility in the amino acids that bind to NAA compared with the native protein. Thus, the present study showed that the majority of the substrate-binding amino acids in those 15 mutants displayed loss of flexibility, which could be the theoretical explanation of decreased binding affinity between the mutant aspartoacylases and NAA. missense mutation, Canavan's disease, aspartoacylase, NAA, flexibility Citation:Sreevishnupriya K, Chandrasekaran P, Senthilkumar A, et al. Computational analysis of deleterious missense mutations in aspartoacylase that cause Canavan's disease.

A computational approach to analyze the missense mutations in human angiogenin variants leading to amyotrophic lateral sclerosis BJP IntroductionAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by selective destruction of motor neurons, resulting paralysis in stages and death within a few years from onset (Bruijin et al., 2004). In the past decade, a small number of genes involved in the etiology of the disease have been identified. Angiogenin (ANG), which encodes an angiogenic protein, has been recently identified as a candidate susceptibility gene for ALS in the Irish and Scottish population by Greenway et al (Greenway et al., 2004).The ANG gene provides instructions for making a protein called angiogenin. This protein promotes the formation of new blood vessels from pre-existing blood vessels through a process called angiogenesis. The ANG gene is located on the long (q) arm of chromosome 14 between positions 11.1 and 11.2. More precisely, the ANG gene is located from base pair 21,152,335 to base pair 21,162,344 on chromosome 14.The protein aggregation, defective axonal transport, oxidative stress, dysfunctional growth factor signaling, mitochondrial dysfunction and excitotoxicity are some of the factors found to be combined to the inception of ALS.Around 10% of ALS cases are inherited genetically, but the other 90% have no clear genetic cause (Dion et al., 2009 AbstractThe most deleterious missense mutations of angiogenin forming amyotrophic lateral sclerosis were identified computationally and the substrate binding efficiencies of these mutations were also analyzed. Out of 12 variants, IMutant2.0, SIFT and PolyPhen programs identified 3 variants that were less stable, deleterious and damaging respectively. These 3 variants were modeled to find their conformational changes in concern with native angiogenin through RMSD calculation and Total energy. Docking of native and 3 mutants with ribonuclease inhibitor was performed to describe the binding efficiencies of those detrimental missense mutations. By computing the binding amino acids' flexibility of angiogenin and computing the binding free energy (ΔG)between native and mutant complexes, the loss in binding affinity with their interacting protein namely ribonuclease inhibitor was investigated. This work is licensed under a Creative Commons Attribution 3.0 License. You are free to copy, distribute and perform the work. You must attribute the work in the manner specified by the author or licensor. Article Info

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