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CCP4BB  September 2008

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Subject:

Re: interface energetics

From:

Steven Darnell <[log in to unmask]>

Reply-To:

Steven Darnell <[log in to unmask]>

Date:

Fri, 12 Sep 2008 11:31:29 -0500

Content-Type:

text/plain

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Andreas,

Thanks for clarifying the situation. I have one other suggestion you can 
think about based on your description of a "monomeric hybrid." Since you 
are mutating your original yeast protein sequence to human/yeast 
chimeras, you could directly model the mutations in Rosetta and skip the 
homology modeling. Of course, this assumes you are not introducing 
deletions or insertions. This approach will also calculate a DDG for you 
automatically.

Your mutation combinations can be defined by creating a "resfile," and a 
standard Rosetta command call can automate the entire process.

http://www.rosettacommons.org/tiki/tiki-index.php?page=resfile+example


Based on my own experience, I would recommend the following flags:

-Wpack_only, -soft_rep_design: softens the repulsive term and 
accommodates mild clashes between atoms

-ex1, -ex2, -extrachi_cutoff 1: allows rotamers to deviate from their 
most probabilistic side chain conformations

-multi_cool_annealer: compared to Rosetta’s standard annealing scheme, 
multi-cool simulated annealing lowers the system to a cooler temperature 
and considers nearly ten times as many rotamer substitutions before 
selecting a low energy structure

-repack_neighbors: mutated residues and adjacent residues are allowed to 
relax


Here are some other relevant flag combinations with regard to interface 
repacking that you can read up on:

-repack_neighbors and -relax_unbound
-min_interface

Good luck,
Steve


Andreas Förster said the following on 9/12/08 4:42 AM:
> Thanks to all who responded to my question regarding the energetics of 
> a known interface applied to orthogolous dimers.
>
> Steven Darnell asked me for some clarifications. I have the structure 
> of a homodimer, defined the dimerization interface and substituted the 
> residues at said interface with those of each of four human orthologs 
> of the original yeast protein. What I call monomeric hybrids are thus 
> yeast proteins with different humanized dimerization interface. I 
> recombine these monomeric hybrids to give four humanized homodimers 
> and six humanized heterodimers. It is the likelihood that these dimers 
> form that I'm interested in.
>
> Following Diana Tomchick's suggestion, I had PISA analyze the 
> interface of the original dimer and learned that it might be worth to 
> consider one other region besides the main helix.
>
> For modeling of the monomeric hybrid, MODELLER is suggested because it 
> does simulated annealing by default. To get the energetics, Rosetta 
> with the "-interface" or "-ddg_only" flags might be a good tool. I 
> have to read up on the details. An alternative is molecular dynamics 
> in Gromacs.
>
> Thanks for your help.
>
>
> Andreas

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