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

A quantum mechanics/molecular mechanics study of the acylation reaction of TEM1 β-lactamase and penicillanate

“…These facts seem to indicate that the fundamental role of the oxy-anion hole components, the amide backbone of Ala237 and Ser70, is not to decrease the energy barrier of the rate limiting formation of the adduct. Moreover, in a recent work on the solvation of β-lactams we have shown 56 that hydrogen bonds on the carbonyl oxygen can also have the undesirable effect of reinforcing the β-lactam CN bond, which must be broken in the subsequent steps. It has been previously claimed 43 that the role of the oxy-anion hole could be related to maintaining the substrate in the correct orientation and to help in the binding process.…”

“…The enhancement of the nitrogen's ability to form hydrogen bonds in a tetrahedral intermediate was expected on the basis of QM/MM molecular simulations of 2-azetidinone and its hydroxylated complex in aqueous solutions. 56 In that study the hydroxylated form was used as a model structure for the tetrahedral adduct c. For the neutral structure, the radial distribution functions, RDFs, showed the absence of a welldefined solvation shell around the nitrogen atom. The same result was obtained by Gao et al 57 in a QM/MM simulation of formamide.…”

Theoretical Study on the Alkaline and Neutral Hydrolysis of Succinimide Derivatives in Deamidation Reactions

“…The hydrolysis reaction of amidic linkages is a widespread studied reaction. − It has been used as a model for the enzymatic cleavage of the peptide bonds. Even though acids can promote amide hydrolysis, base catalysis has been found to be more efficient. ,, A theoretical study regarding the formation of formamide from ammonia and formic acid molecules has been performed by Oie et al In their study, both concerted and stepwise mechanisms have been examined at various levels of theory.…”

11 Theoretical organic chemistry

“…Pitarch et al used similar methodology to simulate azetidin-2-one in water. 40 The QM^MM simulation of enzymatic reactions is a challenging problem due to the complexity of the potential energy surfaces of such systems. The dynamical treatment of Alhambra et al overcomes this problem by using an embedded cluster model, in which a rigid protein^water framework surrounds a £exible region that incorporates the substrate and a portion of the protein.…”