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of applying an euler rotation to one of the domains about the hinge point. In an optional
third step a short-time dynamical trajectory of the protein is computed using Molecular
Dynamics to equilibrate the protein and correct unnatural atomic positions. By repeating
the second and third steps iteratively an ensemble of physically plausible alternate
conformations can be generated, which can potentially be used to validate possible
interactions of proteins with other cellular entities, to find trajectories of motion, for
assembly of complexes, and for otherwise elucidating biologically relevant motions. As
an application, we show how to use the method to predict the conformational changes
required for small ligand binding, thus addressing the induced fit problem for a
significant class of proteins. This requires adding a flexible-ligand docking step after the
equilibration, and other adjustments. A fitness function is devised which discriminates
generated structures which are similar to the crystallographically observed holo structure.
We demonstrate that for four proteins, the method successfully predicts the correct ligand
binding motion given only an apo structure. For a fifth, the holo structure is predicted
given the structure of the protein bound to another ligand, and is correctly predicted to be
open rather than closed, demonstrating that the method is not unduly biased towards
predicting closed conformations.
Introduction
Conformational changes in proteins can take place in a wide variety of ways, many of
which have not been classified. One important class of motions is shear, in which
stacked regions of the protein can slide without losing contact. The largest class is hinge
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