Binding free energy based analysis of arsenic (+Â 3 oxidation state) methyltransferase with S-adenosylmethionine

Human arsenic methyltransferase (hAS3MT) is identified as the enzyme catalyzing the methylation of arsenic, acting as a carcinogen. Discovery of S-adenosylmethionine (SAM) binding site is essential for understanding the methylation of arsenic. Here, the structure of human arsenic methyltransferase (hAS3MT) is proposed and SAM-hAS3MT complex is optimized using molecular dynamics. Furthermore, hydrogen bond network around SAM is studied for stable structure of hAS3MT and to have an insight into the binding affinity, free energy calculations are performed using Molecular Mechanics energies combined with Poisson-Boltzmann or Generalized-Born Surface Area continuum solvation (MM(PB/GB)SA) methods. The role of each residue contributing to the free energy is explored through energy decomposition analysis. To understand the significance of active site residues, eight mutants of hAS3MT are prepared, mutating the residues reported to have functional significance in experimental studies. Mutants are subjected to alanine scanning analysis to determine crucial residues for SAM binding. The findings may lead to the treatment and prevention of serious health threats caused by arsenic.