Using various dynamics protocols, high-temperature simulations, and various models, the research team succeeded in capturing at room temperature the motions of key molecular residues closely related to pol 's shape changes—when certain phenyl rings flip, when salt bridges form, when catalyst magnesium ions are released, and how other residues follow in motion.

A first look at these motions already helps bridge the gaps in researchers' understanding of pol . For instance, the team has deduced that the thumb's movement does not appear to be the rate-limiting step—the most time-consuming aspect that keeps the process from being completed—in pol 's opening motion. Instead, a particular residue rotation and the binding and release of a catalytic magnesium ion appear to hold up the show. Perhaps even more importantly, the simulations give the first atomic-level view of how the enzyme thumb movement works to achieve DNA replication fidelity.

Still, there's a lot more to be done before researchers get a complete grip on pol 's grip on DNA. The team's work with the Alliance continues.

"Although exciting progress has been made on this polymerase system, many questions remain to be answered, and we hope that the experimentalists will continue to stimulate us," says Schlick. Why do some base mispairings slip through the cracks more often than others? Why do different base pairs have different affinities with the polymerase? How do particular DNA mismatches affect pol ?

"As soon as some questions are answered, others arise, and they're all great challenges," Schlick says. "We hope to tackle some of these exciting problems by combining Broyde's biological modeling expertise and Wilson's biochemical and structural insights with our lab's computational tools."