Enzymatic reactions consist of several steps: (i) a weak binding event of the substrate to the enzyme, (ii) an induced fit or a protein conformational transition upon ligand binding, (iii) the chemical reaction, and (iv) the release of the product. Here we focus on step iii of the reaction of a DNA polymerase, HIV RT, with a nucleotide. We determine the rate and the free energy profile for the addition of a nucleotide to a DNA strand using a combination of a QM/MM model, the string method, and exact Milestoning. The barrier height and the time scale of the reaction are consistent with experiment. We show that the observables (free energies and mean first passage time) converge rapidly, as a function of the Milestoning iteration number. We also consider the substitution of an oxygen of the incoming nucleotide by a nonbridging sulfur atom and its impact on the enzymatic reaction. This substitution has been suggested in the past as a tool to examine the influence of the chemical step on the overall rate. Our joint computational and experimental study suggests that the impact of the substitution is small. Computationally, the differences between the two are within the estimated error bars. Experiments suggest a small difference. Finally, we examine step i, the weak binding of the nucleotide to the protein surface. We suggest that this step has only a small contribution to the selectivity of the enzyme. Comments are made on the impact of these steps on the overall mechanism.