Understanding biological mechanisms in atomic detail will require a great many carefully designed experiments to fully sort out. A complementary approach is to employ powerful statistical procedures to rapidly test a multitude of scientific hypotheses using vast numbers of protein sequences—the cell’s own blueprints for specifying most biological mechanisms. Bayesian inference of evolutionary constraints imposed on functionally divergent proteins can reveal critical pieces of the molecular machinery and thereby suggest likely mechanisms to test experimentally. To illustrate this approach, I explore how DNA polymerase clamp loader ATPases may couple DNA recognition to ATP hydrolysis and clamp loading.
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