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sRMSD has a major limitation that must be kept in mind. In the event that the holo and
starting structures have low structural similarity (e.g. come from different organisms),
this measure can lose meaning to varying degrees. This is clearly demonstrated for
Adenylate Kinase. The holo form is taken from the bovine mitochondrial intermembrane
space, while the apo form is taken from the bovine mitochondrial matrix; the two differ
in sequence and structure and in particular have differ substantially in domain 1 structure.
This can best be appreciated by observing the morph of 2ak3(apo) to 1ak2(holo) on
molmovdb.org(morph ID: 079851-18092). For the reasons mentioned the alignment on
domain 1 is very poor and the generated structure with lowest sRMSD is actually very
different from the holo structure. The structure that minimizes the fitness function, on the
other hand, has the correct domain orientation but has a higher sRMSD. For this protein
and this protein only we do not use sRMSD as a metric of success but instead make only
a qualitative evaluation.
The same problem is encountered for Biotin Carboxylase, where the holo and starting
structures come from different organisms, though the structural differences are not as
severe. For Biotin Carboxylase we do use sRMSD as our benchmark, but again use use a
qualitative evaluation to argue that the generated structure that minimizes the fitness
function is a better approximation of the holo structure than the generated structure that
minimizes sRMSD.
Training the fitness function on Glutamine binding protein (GlnBP)
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