SEMIEMPIRICAL MO STUDY ON MALONYL-COA .2. MALONYL-AMP

A conformational study on malonyl-AMP, a reaction intermediate in the synthesis of malonyl-CoA from malonate and CoA catalyzed by malonyl-Co A synthetase, and dimethyl phosphate (DMP) has been carried out using the semiempirical molecular orbital AM1 method and the hydration shell model. The calculated most favored phosphodiester conformations of DM P, malonyl-AMP, and its anion are gauche-gauche in the unhydrated stat e, which is consistent with the structures experimentally determined f or phospholipids and nucleotides. The intramolecular hydrogen bonds be tween the malonyl group and the ribose moiety appear to play a major r ole in determining the conformations of malonyl-AMP and its anion in t he unhydrated state. However, their preferred conformations are differ ent from each other because of the different pattern of hydrogen bonds . The deprotonation of the carboxylic group of malonyl-AMP allows seve ral conformations feasible for the malonyl moiety, while it restricts the conformation of exocyclic and glycosyl bonds to be more rigid. The negatively larger hydration free energy of the charged carboxylate gr oup causes the conformation of malonate and phosphodiester groups to b e extended, and significantly contributes to the stabilization of the overall conformation of malonyl-AMP anion.