We are currently doing a research project in rosetta aiming at developing methods to predict structures of zinc-binding proteins. Some of the tests are currently being performed on Rosetta@Home now with the newly updated V1.39 application. From the user's view, the most noticeable change will be the graphic in which a protein is folding around a colored sphere, representing the zinc metal ion. And here is a little more background about this project.

A large number of proteins in nature include metal atoms as part of their structures, of which zinc is one of the most commonly employed types. For example, about 3% of the protein sequences inferred from human genome are predicted to contain zinc-binding motifs. Many zinc proteins carry out biologically important functions, including zinc-fingers as transcription factors, matrix metalloproteins involved in cancers and cardiovascular diseases, and zinc proteases as lethal factors in anthrax toxins.

In general, zinc metal in proteins plays either a structural role or a catalytic role. In former cases, it is coordinated by protein sidechains and helps to improve the stability of the structure motif. In latter cases, it employs its unique feature as a transition metal and a positively charge ion to participate in the substrate activation and enzymatic catalysis. Currently, zinc metal has been employed in both structure prediction and protein/enzyme design projects in the Baker laboratory.

For the project of structure prediction of zinc proteins, we are modeling zinc metal ion explicitly during the simulation of ab initio protein folding. One common feature we learned from native zinc-binding(structurally) proteins is that zinc metal ion is coordinated by four protein sidechains, most often, Histidine and Cysteine, in a tetrahedral geometry. That is, zinc is positioned in the center of the tetrahedron, and four itrogen (HIS) or sulfur (CYS) atoms are positioned on the vertexes of the tetrahedron. If you look at the structure displayed on your graphic and color them by CPK (hitting "C" key), you should find out that there are always four either blue (nitrogen of HIS) or yellow (sulfur of CYS) sidechains around the zinc (displayed as sphere). This important zinc coordination motif is implemented as part of rosetta energy function and we are hoping that by combining the explicit zinc metal modeling and Rosetta ab initio prediction method, we can develop a useful method to predict structures accurately for this class of important proteins in nature.

Of course, to achieve this goal, we will have to rely on the generous help of all Rosetta@Home users from all over the world. Feel free to let me know if you have any questions or insights on this project. Happy crunching!

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So, how does zinc metal bond with proteins? Why is that important? what would be an every day recognizable example of zinc metal bonding?

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I moved Stacey's post here where the zinc is already being discussed. So, perhaps he hasn't seen Chu's original post.

Stacey, are you saying that:

...zinc-fingers as transcription factors, matrix metalloproteins involved in cancers and cardiovascular diseases, and zinc proteases as lethal factors in anthrax toxins.

...wasn't entirely clear to you? :) Me either.

I believe the point is that zinc is found in some proteins naturally, and seems to have some unique properties around it when it exists. So, if one can better understand those properties, then perhaps they can learn how to better predict structure for proteins that do happen to include zinc.

Perhaps Chu can give some (more) examples of such proteins, and talk more about the enzyme work being done. Or, better yet, describe what one could do with an improved understanding of zinc-binding proteins as they relate to cancers and cardiovascular diseases.

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Rosetta Moderator: Mod.Sense

So, how does zinc metal bond with proteins? Why is that important? what would be an every day recognizable example of zinc metal bonding?

Stacey,

If I remember correctly, one use is that your pancreas usually does it in the beta cells that make insulin. If this stops, you have type 1 diabetes or an uncommon type such as MODY, and need insulin shots for the rest of your life. I'm looking for more information on this so that I'll have more chance to persuade a few groups of diabetics to participate in Rosetta@home.

I've already started a Google search for such information, but am likely to need a few days to finish the followup to the search and post the results.

I've already started a Google search for such information, but am likely to need a few days to finish the followup to the search and post the results.

I finished the followup sooner than expected. The following web sites show the relation of zinc to diabetes:

Dietary Zinc For Diabetes Prevention Not Backed By Evidence
http://www.sciencedaily.com/releases/2007/01/070128140936.htm

Diabetes Zinc For Diabetes
http://www.healthbulletin.org/diabetes/diabetes5.htm

Dr. Lewis Mehl-Madrona, M.D., Ph.D.
http://www.healing-arts.org/mehl-madrona/mmzinc.htm

Zinc, the Pancreas, and Diabetes: Insights from Rodent Studies and Future Directions
http://www.ingentaconnect.com/content/klu/biom/2005/00000018/00000004/00003686

Zinc and Diabetes
http://www.diabetesselfmanagement.com/blog/Amy_Campbell/Zinc_and_Diabetes

Zinc supplementation for the prevention of type 2 diabetes mellitus
http://www.cochrane.org/reviews/en/ab005525.html

Zinc, Insulin and Diabetes
http://www.jacn.org/cgi/content/full/17/2/109

Summary: More research is needed to pin down the details.

During that search, I also found references to zinc being involved in a number of other conditions.

Antiviral Protein May Inhibit Ebola And Marburg Virus, New Study Suggests
http://www.sciencedaily.com/releases/2007/03/070319174933.htm

Cochrane Search Results - Zinc
http://search.cochrane.org/search?q=zinc&restrict=cochrane_org&scso_cochrane_org=whole+site&scso_review_abstracts=Cochrane+reviews
Don't expect all the links this finds to be accessible to the public.

Metal protein attenuating compounds for the treatment of Alzheimer's disease
http://www.cochrane.org/reviews/en/ab005380.html

Another article on a zinc-binding protein:

Zinc Transporters Regulate Pancreatic Cancer
http://www.sciencedaily.com/releases/2007/11/071112172150.htm

Another protein that binds to zinc, metallothionen:

http://www.ingentaconnect.com/content/apl/tbmk/2001/00000006/00000002/art00002?crawler=true

http://www.tangledneuron.info/the_tangled_neuron/genetics/

http://www.alternativementalhealth.com/articles/pyroluria.htm

http://www.hputest.nl/lit108.doc

http://www.springerlink.com/content/v1077829723q14n0/

http://cat.inist.fr/?aModele=afficheN&cpsidt=11226032

Also binds to a few more types of metal ions, such as copper and cadmium.

Has some effect on schizophrenia.

More proteins that bind to zinc:

Metalloenzymes, such as carbonic anhydrase, alkaline phosphatase, RNA & DNA polymerases, thymidine kinase and carboxypeptidases
http://www.cdhb.govt.nz/chlabs/help/4227hlp.htm

DrZIP1
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1183453

ZIP4 and pancreatic cancer
http://www.sciencedaily.com/releases/2007/11/071112172150.htm

MPAC and Alzheimer's
http://www.cochrane.org/reviews/en/ab005380.html

Could we have some indication if which other metal ions minirosetta can now handle binding to proteins? For example, some which can bind are copper, cadmium, cobalt, iron and magnesium.

Are any more of these planned for the future?

I showed this to my colleague in the office (who has a Chemistry degree), who said. "Cool... I can't believe no-one in that [this] thread has mentioned the common cold". Binding to zinc to cure/alleviate the common cold?

I showed this to my colleague in the office (who has a Chemistry degree), who said. "Cool... I can't believe no-one in that [this] thread has mentioned the common cold". Binding to zinc to cure/alleviate the common cold?

I did a Google search to check that and found that the evidence for zinc helping the common cold in inconclusive, but there have been a number of lawsuits from people who lost their sense of smell, their sense of taste, or both, while trying it. I didn't spot any evidence that any protein binding to zinc is involved in either the common cold or the loss of those senses.

http://www.mayoclinic.com/health/cold-remedies/ID00036

http://www.flupatrol.com/2006/12/13/debate-over-zicam-does-risk-outweigh-the-benefits/

http://www.usatoday.com/money/industries/health/2007-08-01-zicam_N.htm

http://www.snopes.com/medical/drugs/zicam.asp

http://www.washingtonpost.com/wp-dyn/content/article/2006/01/30/AR2006013001255.html

http://www.uspharmacist.com/oldformat.asp?url=newlook/files/alte/feat2.htm

http://www.ncbi.nlm.nih.gov/pubmed/8942045

http://en.wikipedia.org/wiki/Zinc_gluconate

Looks like a zinc-binding non-protein may be significant in cancer research.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B7GJC-4NBXVFH-1&_user=4420034&_origUdi=B6T6R-4FH4V4G-3&_fmt=high&_coverDate=06%2F01%2F2007&_rdoc=1&_orig=article&_acct=C000063005&_version=1&_urlVersion=0&_userid=4420034&md5=9b678a0dca8165abdc9fb5caf8392016

Can your software handle this?

It's also cadmium-binding, so you may want to check if your software can handle that too.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T6P-4KSHB9D-D&_user=4420034&_origUdi=B7GJC-4NBXVFH-1&_fmt=high&_coverDate=02%2F28%2F2007&_rdoc=1&_orig=article&_acct=C000063005&_version=1&_urlVersion=0&_userid=4420034&md5=ea2e3395765b8abe9725eca4d51a2379

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TCP-4RV7YC9-1&_user=4420034&_origUdi=B6T6P-4KSHB9D-D&_fmt=high&_coverDate=06%2F30%2F2008&_rdoc=1&_orig=article&_acct=C000063005&_version=1&_urlVersion=0&_userid=4420034&md5=933e43cc788f991b204830e46a0266f7

News on matrix metalloproteases (a family of zinc-linked proteins, known as MMPs) and cancer:

http://cat.inist.fr/?aModele=afficheN&cpsidt=17774634

http://www.ncbi.nlm.nih.gov/pubmed/15362860?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=1&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/11382769?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=4&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/15273280?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/10202187?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=4&log$=relatedreviews&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/10995877?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/11241310?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=1&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/11716069?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedreviews&logdbfrom=pubmed

http://pubs.acs.org/doi/abs/10.1021/pr050483b

http://www.comparative-hepatology.com/content/3/s1/s20

http://www.ncbi.nlm.nih.gov/pubmed/10989641?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/9880540?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/12614260?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/10357558?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedreviews&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/10365151?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=4&log$=relatedreviews&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/11053050?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=3&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/9087449

http://www.ncbi.nlm.nih.gov/pubmed/11278623?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=3&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/12714042?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=4&log$=relatedreviews&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/15781320?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedreviews&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/12706853?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedreviews&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/11381077?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/11716070?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedreviews&logdbfrom=pubmed

http://en.wikipedia.org/wiki/Metalloproteinase

http://www.ncbi.nlm.nih.gov/pubmed/12067201?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=3&log$=relatedreviews&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/11956636?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedreviews&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/10389763?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/10491431?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=3&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/10415741?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedreviews&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/12810672?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=3&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/11716072?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedreviews&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/17156449?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/12592384?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed

A slow site:
http://biblioteca.universia.net/html_bura/ficha/params/id/35284772.html

Great data mining work, robertniles! Thank everyone for such a wonderful discussion. Definitely all the other metals are our to-do list and we are very excited about introducing for the first time metal into Rosetta structure modeling. As mentioned in my original post, Zinc is one of the most abundant metals found in natural protein molecules, playing both important structural (stabilizing proteins) and catalytic (helping realize protein functions) roles. A lot of zinc-binding proteins are involved in DNA binding and recognition and the most popular structure motif is referred as "zinc finger". For example, an enzyme called Integrase in HIV virus has a structural domain that contains zinc-binding sites and is believed to be responsible for multimerization of this enzyme. To understand how the zinc binding affect this process will certainly help us find new insights to fight against HIV. I am glad to see the last post mentions matrix metalloproteases because I am soon to join a new lab which have done a lot of work in characterizing unknown MMPs in human proteomics which are believed to be cancer related. I am very grateful to everyone's contribution to our project and I will surely keep everyone posted when there is any exciting results we will obtain in future.

Could we have some indication if which other metal ions minirosetta can now handle binding to proteins? For example, some which can bind are copper, cadmium, cobalt, iron and magnesium.

Are any more of these planned for the future?

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A web site video on a cancer-treatment method still under development that may link to your work on metal-binding proteins, at least if they're able to use metal-binding proteins instead of the metal nanoparticles they're trying now:

http://www.hybridmedicalanimation.com/60min.html

Definitely all the other metals are our to-do list and we are very excited about introducing for the first time metal into Rosetta structure modeling.

Could we have some indication of which other metal ions minirosetta can now handle binding to proteins? For example, some which can bind are copper, cadmium, cobalt, iron and magnesium.

Are any more of these planned for the future?

Is mercury also on the list planned for the future? If it is, I'll try to use that to attract some people interested in autism-related conditions to participate in Rosetta@home.

If I decide to start new threads on why proteins binding to other metal ions are important, where would you like me to put them? I've already found a number of web sites to mention.

If I decide to start new threads on why proteins binding to other metal ions are important, where would you like me to put them? I've already found a number of web sites to mention.

I would put such links and discussion here on the science board. Thanks in advance for taking the time to collect and post such interesting info.

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Rosetta Moderator: Mod.Sense

Another zinc-binding protein, this one related to HIV and the structure of the (human) cell nucleus:

ZMPSTE24

http://www.mooshee.com/health-news/mooshee-com-health-news-study-finds-hiv-protease-inhibitor-drugs-may-adversely-affect-the-scaffolding-of-the-cell-nucleus

An idea to think of for handling proteins that bind to other metal ions:

Create a module similar to the one for handling zinc ions, but with more adjustment parameters so that you can make it handle a wide variety of metal ions.

Then, if you need to handle any proteins bound to at least two types of metal ions, just include two or more of these modules in future versions of minirosetta, but instruct them to get their parameters from different files.