Energetic analysis of Bcl-X_L pocket opening.

<p>(<b>A</b>) Conformations generated without the use of a biasing potential (<i>solid green line</i>) show a similar distribution of energies to those generated with the biasing potential at a randomly selected target residue (<i>dashed black line</i>); increasing the strength of the biasing potential here leads to conformations with higher energies (<i>solid black line</i>). In contrast, application of the biasing potential at the protein interaction site (<i>red lines</i>) leads to conformations with a distribution of energies that strongly overlaps with those energies of conformations sampled in the unbiased simulations, suggesting that these conformations represent low-energy states accessible to the unbound protein. (<b>B</b>) A scatterplot showing the deep pocket volume for conformations generated with the biasing potential applied to one of the random sites (<i>moderate bias in cyan, strong bias in blue</i>) or to the protein interaction site (<i>moderate bias in red, strong bias in orange</i>). Low-energy conformations containing large pockets are sampled only if the biasing potential it is applied at the protein interaction site; while large pockets are sampled using the strong bias at random sites, these conformations have considerably higher energy. All energies shown here were evaluated in the absence of the biasing potential, for fair comparison.