[phenixbb] Modeling Disordered Domains

[Damian Ekiert]

Perhaps inspired by the fierce debate on this BB and elsewhere about  
how to model disordered side chains, I would like to present the  
following scenario (my current refinement project):

The structure was solved by molecular replacement, is 3.25Å  
resolution, and ~70% solvent.  I have 6 copies of a large complex in  
the AU (~100kDa per protomer).  Only one copy is fully ordered.  In  
the other 5 copies, a entire domain (~25kDa) is largely disordered  
(some have patchy residual density, but not readily interpretable).   
Altogether, this means that I am missing ~20% of the total protein in  
the AU.  It seems that how you model this much "missing" material  
could have a significant effect on the final refined model.  This is  
something we have observed a number of times, so I am wondering if  
anyone can suggest ways to deal with this aside from just leaving the  
domains out entirely.

In this case, the missing domain is connected by two short hinges that  
restrict the rotational degrees of freedom considerably (you can think  
of the missing domains as a door--it can only pivot about the hinge,  
can't be flipped upside-down or sideways, etc., and is anchored close  
to the door frame).  Additionally, crystal packing and steric  
constraints restrict the "sweep" of the missing domains to further  
pinpoint their location.

Is it worth trying to model this?  My impression from some earlier  
posts was that most people were content for disordered regions to be  
modeled as bulk solvent (rather than fiddling with masks to also cover  
the expected location of protein, etc.), but I wonder if you may  
actually substantially improve the model when this much protein is  
disordered.  I guess I am imagining something analogous to a rigid  
body fit to the mean position of the disordered domains and a TLS-like  
ADP description of the motion (with a very large magnitude to account  
for the large displacement), but I am open to suggestions.

On a final note, regarding those pesky missing side chains: any  
thoughts on trying to employ a "Ringer"-like approach to model some of  
these (Fraser, et al., Nature 2009, 462(7273):669-673)?  Is this  
practical (maybe this would add to many additional parameters)?

Best,

Damian Ekiert