[Chimera-users] Request for assistance

[Elaine Meng]

Hi Zachary,
Congratulations on your recent work and publications, and thanks for your kind words!

Chimera does not have tools for detailed prediction of changes in a protein's conformational ensemble or in free energy of binding or folding upon mutation.  Chimera tools allow first-order estimations of mutation impact such as loss of H-bonds or creation of steric clashes in the wild-type conformation or binding pocket.  

For more detailed calculations of a protein's energy landscape, one would generally perform extensive simulations with some package such as AMBER, GROMACS, or CHARMM (just to name a few… ).  This is computationally expensive and requires some expertise.  If not done well, the results can be useless.  Alternatively, there are less computationally intensive approaches that estimate the impacts of mutations with some heuristics and/or empirical parameter values, and these vary widely in methodology and accuracy.  I haven't used these myself, I only know of their existence from seeing various publications.  Some are even available as web servers, and here are just a few I found just now with web search.  (this is not an endorsement since I haven't used them nor studied the related publications)

<http://www.ics.uci.edu/~baldig/mutation.html>
<http://mordred.bioc.cam.ac.uk/sdm/sdm.php>
<http://rosie.rosettacommons.org>

I hope this helps,
Elaine
----------
Elaine C. Meng, Ph.D. 
UCSF Computer Graphics Lab (Chimera team) and Babbitt Lab
Department of Pharmaceutical Chemistry
University of California, San Francisco

On Jun 4, 2013, at 8:49 AM, "Zachary W. Carpenter" <ZWC2101 at columbia.edu> wrote:

> Dear Chimera, 
> I have been a long time user and really love your software. Recently I have used and cited Chimera in 4 high impact publications. One in mBio, two in nature medicine, and a final one in review at Nature Genetics. I have used Chimera to make beautiful images of mutations that we identify in NGS data of tumors. My role has become interpreting the effects of mutations on crystal structure. Thus far this has not been difficult as the effects of the mutations have been obvious. A recent finding however has left me extremely perplexed and I have need for greater accuracy of structural modeling of the mutations. I was wondering if you can put me in the right direction for creating models of mutations that are more reliable then just using Modeller or I-Tasser with the mutant in the sequence to be predicted. I know this is an elaborate question but I'd like to know which Chimera tools I can use to help me along this path. Or if I need to use totally new software/ methods. 
> Thanks for your time, 
> Zach 
> 
> 
> -- 
> Zachary W. Carpenter
> Department of Pharmacology
> College of Physicians and Surgeons
> Columbia University
> 630 West 168th Street
> New York, NY 10032
> 
> Email: ZWC2101 at Columbia.edu
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