SIMULATION ANALYSIS OF FORMYCIN 5'-MONOPHOSPHATE ANALOG SUBSTRATES INTHE RICIN A-CHAIN ACTIVE-SITE

Ricin is an RNA N-glycosidase that hydrolyzes a single adenine base fr om a conserved loop of 28S ribosomal RNA, thus inactivating protein sy nthesis. Molecular-dynamics simulation methods ae used to analyze the structural interactions and thermodynamics that govern the binding of formycin 5'-monophosphate (FMP) and several of its analogs to the acti ve site of ricin A-chain. Simulations are carried out initiated form t he X-ray crystal structure of the ricin-FMP complex with the ligand mo deled as a dianion, monoanion and zwitterion. Relative changes in bind ing free energies are estimated for FMP analogs constructed from amino substitutions at the 2- and 2'-positions, and from hydroxyl substitut ion at the 2'-position.