Carboxyphosphate is a key intermediate in de novo purine and pyrimidine biosynthesis. Inhibiting this pathway is novel and could lead to the creation of new antifungal and antimicrobial agents. The short half-life of carboxyphosphate makes it difficult to study experimentally. Various models have been used to simulate the decarboxylation of carboxyphosphate in aqueous solution. Ab initio dynamics simulations were performed, using the TeraChem program, on the pseudo-chair monoanion embedded in a sphere of water molecules with spherical boundary conditions using B3LYP/6-31G(d). Four different models have been used, varying the number of water molecules in the simulation while also varying how many water molecules are treated quantum mechanically. The first model is all QM, another is QM/MM treating only carboxyphosphate QM, the third includes the first hydration shell in the QM region. These first three models contain ~100 waters. The last QM/MM model has 60 waters where two waters and carboxyphosphate are QM. The observed conformational changes for carboxyphosphate have been different for each model. Proton transfer within the intramolecular hydrogen bond of carboxyphosphate can occur with or without the involvement of a QM water.

Ab initio dynamics of the unfolding and decarboxylation of pseudo-chair carboxyphosphate in aqueous solution

249th National Meeting (2015)

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