Many parasitic organisms are incapable of synthesizing the purine and pyrimidine nucleotides necessary for DNA synthesis. Instead, they scavenge these molecules from the host organism through various biochemical pathways. One such enzyme involved in these pathways is a purine phosphoribosyltransferase, which catalyzes the combination of a nucleotide base and a ribosylphosphate to form a nucleotide. We carried out molecular dynamics calculations to compare a human phosphoribosyltransferase with its analog from the protozoan Tritichomonas foetus. While the human enzyme is highly selective, the parasite enzyme operates with comparable efficiency on a number of different substrates. Our simulations show that this is due to a high degree of flexibility in the parasite substrate-binding pocket, and also allowed us to rationalize the effects of several known mutations. The resources of the Computer Graphics Laboratory are used to visualize the enzyme-substrate complexes from our simulations.
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