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@Columbia.edu
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@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@Columbia.edu _______________________________________________ Chimera-users mailing list Chimera-users@cgl.ucsf.edu http://plato.cgl.ucsf.edu/mailman/listinfo/chimera-users
Hey Elaine, Thanks for your quick response. Are you aware of any tutorials or wiki type instruction guides to getting started with more complex computational approaches to what I am describing? Best, Zach On Tue, Jun 4, 2013 at 1:02 PM, Elaine Meng <meng@cgl.ucsf.edu> wrote:
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@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@Columbia.edu _______________________________________________ Chimera-users mailing list Chimera-users@cgl.ucsf.edu http://plato.cgl.ucsf.edu/mailman/listinfo/chimera-users
-- Zachary W. Carpenter Department of Pharmacology College of Physicians and Surgeons Columbia University 630 West 168th Street New York, NY 10032 Email: ZWC2101@Columbia.edu
Hi Zach, Sorry, not off the top of my head. Potential sources of information: - websites, documentation and user mailing lists or helpdesks for simulation packages, e.g. for AMBER: http://ambermd.org/ http://ambermd.org/#reflector http://ambermd.org/tutorials/ … and analogous for other programs - journal article materials & methods sections, especially in respected journals from groups that specialize in computational chemistry (and are thus more likely to know what they're doing :-) ) - general comp-chem discussion groups, e.g. could ask questions on CCL.net Before you start sending emails or formulating pubmed queries, I recommend thinking more about what exactly you want to predict. Do you want to predict change in stability, or in free energy of binding some ligand, or just what the protein might "look like" (probable conformations) with the mutation? Is a precise quantitative result important? It is best to ask as specific questions as possible, because if they are too broad or vague people are less likely to respond. If you don't require quantitative results (e.g. free energy of folding decreased by N kcals/mol), less computationally intensive approaches may be the way to go… unfortunately either way will require a fair amount of legwork because of the vast number of possibilities. Brief searching turned up this review, and surely there are others <http://www.ncbi.nlm.nih.gov/pubmed/20033914> Another thing to consider seriously is seeking collaboration (or at least advice) from expert computational chemists, e.g. Friesner group at Columbia. Best, Elaine On Jun 4, 2013, at 1:35 PM, "Zachary W. Carpenter" <ZWC2101@columbia.edu> wrote:
Hey Elaine, Thanks for your quick response. Are you aware of any tutorials or wiki type instruction guides to getting started with more complex computational approaches to what I am describing? Best, Zach
participants (2)
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Zachary W. Carpenter