Modeling beta-lactam interactions in aqueous solution through combined quantum mechanics-molecular mechanics methods

Ln this article, we have carried out a series of theoretical computations i ntended to analyze the interactions of beta-lactam compounds in aqueous sol ution. The final aim is to rationalize the influence of the medium on beta- lactam antibiotics reactivity. In particular, the hydrolysis reaction has b een studied because of the considerable interest due to its relationship wi th resistance mechanisms developed by bacteria. The study is extended to th e simplest beta-lactam molecule, propiolactam or 2-azetidinone, and to the corresponding hydroxylated complex (resulting from the addition of a hydrox yl anion to the carbonyl group) that plays a crucial role in hydrolysis pro cesses. Molecular Dynamics simulations have been tarried out using a hybrid quantum mechanics-molecular mechanics potential: the solute is described u sing the density functional theory, whereas water solvent molecules are tre ated classically. This represents a sophisticated computational level which , compared to usual force-field simulations, has the advantage of allowing a detailed analysis of solute's electronic properties. The discussion of re sults is focused on the role played by solute-solvent hydrogen bonds and so lvent fluctuations on solute's structure. (C) 1999 John Wiley & Sons, Inc.