Homology modeling of Homo sapiens lipoic acid synthase: Substrate docking and insights on its binding mode

J Theor Biol. 2017 May 7;420:259-266. doi: 10.1016/j.jtbi.2016.09.005. Epub 2016 Oct 5.


Lipoic acid synthase (LIAS) is an iron-sulfur cluster mitochondrial enzyme which catalyzes the final step in the de novo pathway for the biosynthesis of lipoic acid, a potent antioxidant. Recently there has been significant interest in its role in metabolic diseases and its deficiency in LIAS expression has been linked to conditions such as diabetes, atherosclerosis and neonatal-onset epilepsy, suggesting a strong inverse correlation between LIAS reduction and disease status. In this study we use a bioinformatics approach to predict its structure, which would be helpful to understanding its role. A homology model for LIAS protein was generated using X-ray crystallographic structure of Thermosynechococcus elongatus BP-1 (PDB ID: 4U0P). The predicted structure has 93% of the residues in the most favour region of Ramachandran plot. The active site of LIAS protein was mapped and docked with S-Adenosyl Methionine (SAM) using GOLD software. The LIAS-SAM complex was further refined using molecular dynamics simulation within the subsite 1 and subsite 3 of the active site. To the best of our knowledge, this is the first study to report a reliable homology model of LIAS protein. This study will facilitate a better understanding mode of action of the enzyme-substrate complex for future studies in designing drugs that can target LIAS protein.

Keywords: Fsfemtoseconds; GAgenetic algorithm; Homology model; Ins2Akita/+accelerated nephropathy; KGDHα-ketoglutarate dehydrogenase; LAlipoic acid; LIASlipoic acid synthase; Lipoic acid; Lipoic acid synthase; MDmolecular dynamics; NVTconstant volume and normal temperature; ORFopen reading frame; PDHCpyruvate dehydrogenase complex; Pspicoseconds; RMSDroot mean square deviation; RMSFthe root mean square fluctuation; S-Adenosyl Methionine; SAM-Sadenosyl methionine; T2DMtype 2 diabetes mellitus; Thermosynechococcus elongatus; apoE−/−apo E deficient.

MeSH terms

  • Catalytic Domain
  • Computational Biology / methods
  • Humans
  • Models, Molecular*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • S-Adenosylmethionine / chemistry
  • Sequence Homology, Amino Acid*
  • Structural Homology, Protein
  • Sulfurtransferases / chemistry*
  • Thioctic Acid / biosynthesis


  • Thioctic Acid
  • S-Adenosylmethionine
  • Sulfurtransferases
  • lipoic acid synthase