The first step of the reaction catalysed by the enzyme citrate synthase is studied here with high level combined quantum mechanical/molecular mechanical (QM/MM) methods (up to the MP2/6-31+G(d)//6-31G(d)/CHARMM level). In the first step of the reaction, acetyl-CoA is deprotonated by Asp375, producing an intermediate, which is the nucleophile for attack on the second substrate, oxaloacetate, prior to hydrolysis of the thioester bond of acetyl-CoA and release of the products. A central question has been whether the nucleophilic intermediate is the enolate of acetyl-CoA, the enol, or an 'enolic' intermediate stabilized by a 'low-barrier' hydrogen bond with His274 at the active site. The imidazole sidechain of His274 is neutral, and donates a hydrogen bond to the carbonyl oxygen of acetyl-CoA in substrate complexes. We have investigated the identity of the nucleophilic intermediate by QM/MM calculations on the substrate (keto), enolate, enol and enolic forms of acetyl-CoA at the active site of citrate synthase. The transition states for proton abstraction from acetyl-CoA by Asp375, and for transfer of the hydrogen bonded proton between His274 and acetyl-CoA have been modelled approximately. The effects of electron correlation are included by MP2/6-31G(d) and MP2/6-31+G(d) calculations on active site geometries produced by QM/MM energy minimization. The results do not support the hypothesis that a low-barrier hydrogen bond is involved in catalysis in citrate synthase, in agreement with earlier calculations. The acetyl-CoA enolate is identified as the only intermediate consistent with the experimental barrier for condensation, stabilized by conventional hydrogen bonds from His274 and a water molecule.