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distorted domains, and does not resemble the holo. The inclusion of the domain
distortion and stability terms counters this problem. The gyration radius appears squared
for the physical reasons metioned earlier and to strongly penalize structures that minimize
docked energy but which bind the ligand by forming a new cleft not observed
experimentally, e.g. by pinching shut the region behind the hinge. In the latter situation a
structure is seen that is much like a clam opened to a very wide angle.
The structure with highest stability, inset 5.3.g, is quite close to the starting structure.
This should not be surprising, since such structures have gone through a minimum of
structural manipulation and so have low steric strain. Stability is another measure whose
point is not to exclusively pinpoint the predicted holo structure, but rather to exclude
from consideration structures which minimize docked energy but which have
entropically or entalphically unfavorable conformations.
Based on these considerations we parameterized the fitness function.
fitness_function = (docked_energy +foldx_energy/10 + gyration_radius 2 /10 + D3RMSD_aligned + D1RMSD_aligned)
The stability or foldx_energy term was noisy and favored the apo structure, therefore we
reduced it by a factor of
1
, which still gave us the ability to weed out unphysical
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conformations. Similarly the gyration radius term too strongly favored interpenetrating
domains and was ! reduced by the same factor, which still let it retain its ability to weed
out excessively-open conformations. D3RMSD_aligned is the RMSD of domain 3 of the
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