Without DNA, the thumb is closed. This joint-like flexibility of the thumb region has implications for HIV transcription and for the possibility of designing drugs to stop it. Some biologists believe that one class of RT-inhibitor drugs works by lodging in the palm of the active subdomain, like sand in a gear, locking the thumb in open position, so the enzyme can't function normally. From crystallographic studies, researchers in effect had still photographs of a molecular hand in two positions. What they lacked was knowledge of how the thumb moved, a molecular movie, which is what Madrid's specialty, molecular dynamics could provide.
Some crystallographers say the correct native state is with the thumb up.
This image from the simulations shows the thumb subdomain in motion toward the fingers, which remain stationary. But worth a try. For the simulation, Madrid removed the DNA coordinates, so the starting structure was thumbs-up. To get reliable results, Madrid ran eight simulations, each of which required 41 hours of computing time on 16 CRAY T3E processors. For six of the eight, the structure closed its thumb, strongly suggesting this is the native state.