Computer modeling and molecular dynamics simulations of ligand bound complexes of bovine angiogenin: Dinucleotide topology at the active site of RNase a family proteins

We have undertaken the modeling of substrate-bound structures of angiogenin . In our recent study, we modeled the dinucleotide ligand binding to human angiogenin. In the present study, the substrates CpG, UpG, and CpA were doc ked onto bovine angiogenin. This was achieved by overcoming the problem of an obstruction to the BI site by the C-terminus and identifying residues th at bind to the second base. The modeled complexes retain biochemically impo rtant interactions. The docked models were subjected to I ns of molecular d ynamics, and structures from the simulation were refined by using simulated annealing. Our models explained the enzyme's specificity for both BI and B 2 bases as observed experimentally. The nature of binding of the dinucleoti de substrate was compared with that of the mononucleotide product. The mode ls of these complexes were also compared with those obtained earlier with h uman angiogenin. On the basis of the simulations and annealed structures, w e came up with a consensus topology of dinucleotide ligands that binds to h uman and bovine angiogenins. This dinucleotide conformation can serve as a starting model for ligand-bound complex structures for RNase A family of pr oteins. We demonstrated this capability by generating the complex structure of CpA bound to eosinophil-derived neurotoxin (EDN) by fitting the consens us topology of CpA to the crystal structure of native EDN. (C) 2001 Wiley-L iss, Inc.