HIV-1's protease enzyme mutates to elude drugs that block its active site, but some mutations occur outside the active-site cavity and are not well understood. To picture how such mutations might lead to drug resistance, a team led by Gail E. Fanucci of the University of Florida and Carlos Simmerling of the State University of New York, Stony Brook, combined electron paramagnetic resonance (EPR) spectroscopy with molecular dynamics simulations (J. Am. Chem. Soc., DOI: 10.1021/ja807531v). Other teams have surmised that the mutations affect the mobility of two gate-keeping molecular flaps near the active site. To test that idea, Fanucci's team used EPR to measure how the distribution of distances between flaps changes in different drug-resistant HIV-1 proteases. Simmerling's team then built a computer model that jibed with the EPR data and provides a molecular view of how the proteases move around. The mutations alter the flaps' flexibility, possibly changing the way the gate engages inhibitors, the team says.