Computer modeling of human angiogenin-dinucleotide substrate interaction

Structures of substrate bound human angiogenin complexes have been obtained for the first time by computer modeling. The dinucleotides CpA and UpA hav e been docked onto human angiogenin using a systematic grid search procedur e in torsion and Eulerian angle space. The docking was guided throughout by the similarity of angiogenin-substrate interactions with interactions of R Nase A and its substrate. The models were subjected to 1 nanosecond of mole cular dynamics to access their stability. Structures extracted from MD simu lations were refined by simulated annealing, Stable hydrogen bonds that bri dged protein and ligand residues during the MD simulations were taken as re straints for simulated annealing. Our analysis on the MD structures and ann ealed models explains the substrate specificity of human angiogenin and is in agreement with experimental results. This study also predicts the B2 bin ding site residues of angiogenin, for which no experimental information is available so far. In the case of one of the substrates, CpA, we have also i dentified the presence of a water molecule that invariantly bridges the B2 base with the protein. We have compared our results to the RNase A-substrat e complex and highlight the similarities and differences. Proteins 2001; 42 :125-135. (C) 2000 Wiley-Liss, Inc.