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lengths and angles)[89]. The equilibration step may also be skipped for some
applications to save computer time, while still yielding useful information.
We demonstrate that as one application of the method, we can predict the ligand bound,
or holo, state of a structure given only the ligand and the coordinates of the protein in the
apo state, or bound to a different ligand. The exploration of phase space is performed in
such a way as to minimize a fitness function which includes terms measuring the radius
of gyration, free energy of folding, protein-ligand binding energy, and domain distortion.
We will more formally define all of these terms later in this work, and only briefly
introduce and motivate them now.
Protein-ligand binding energy, or docked energy, was found early on to have significant
ability to discriminate between near-holo structures and decoys. However some decoys
were so distorted that new clefts were generated which ligands bound to with high
affinity. We also found that this measure did not vary smoothly with sRMSD (a measure
of distance from the holo structure, which we define later). For these reasons we added
terms to the fitness function as follows.
Radius of gyration typically decreases during the cleft closure often associated with
ligand binding, as has been observed by Small Angle X-ray Scattering (SAXS)[119,120],
and as we will further demonstrate here. Radius of gyration also varies smoothly with
sRMSD, and so helps deal with the noise issues mentioned above and leads to improved
convergence. However radius of gyration alone is not a good predictive measure because
it is trivially possible to it with an unstable protein structure consisting of distorted
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