Proteopedia - User contributions [en]

Proteopedia:Wishlist

2009-02-02T19:41:51Z

Greg Black:

This is the page to list features you wish Proteopedia had. As Proteopedia grows and develops, we will try to include the best and most appropriate ideas.

If you want to report a problem in an existing feature, please do so at [[Proteopedia:Problems]].

When adding a suggestion, please identify yourself by adding <nowiki>~~~~</nowiki> at the end. This is wikitext that is converted into your name and the date.

This list has the most important items at the top.
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*'''SOLVED:''''' There is now a link to FirstGlance underneath the molecule for every automatically seeded page.'' In every article titled with a single PDB id code, a link to (for a random case) "Explore 2ace" that goes to '''FirstGlance in Jmol'''. The link syntax is [http://bioportal.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ace http://bioportal.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ace].
* '''Searching''' for a '''plural''' should find the '''singular''' match, and vice versa. For example: I searched for "histocompatibility antigens" and did not find the page "Category: Histocompatibility antigen". Searching for "histocompatibility antigen" did find this page. [[User:Emartz|Emartz]] 19:00, 8 March 2008 (IST)
* '''Color keys''' displayed beneath Jmol, changing as needed with each green link. For example "alpha helix" and "beta strand" colored in the standard Jmol secondary colors. The standard keys should be pre-built and callable by name, perhaps by a parameter in the <scene ...> tag. [[User:Emartz|Emartz]] 01:59, 19 March 2008 (IST) This is a really good idea! I've had to go to other sites to figure out what things stand for and was actually wondering if there was a way to make a key, but I guess not right now. [[User:Emily Forschler|Emily Forschler]] 03:14, 6 June 2008 (IDT)
* '''Biological units''' (from RCSB) should be the default initial scenes, with a view of the asymmetric unit optional, as agreed in discussion. Eric Martz plans to provide a mock-up of an advanced page that would have views from EBI PQS, EBI PISA, and RCSB biological units, with brief explanations of each.
* '''ConSurf coloring''' can be provided as discussed with Nir Ben-Tal and Elana Erez. This could be one of the standard scenes on the proposed menu of standard scenes.
* '''Several standard scenes''', such as those in FirstGlance in Jmol, could be provided in a pull-down menu on the auto-seeded pages. It could be one more row in the table below Jmol. Eric Martz plans to provide the scripts and HTML color keys for these. [[User:Eric Martz|Eric Martz]] 19:54, 13 April 2008 (IDT)
* '''All models in NMR ensembles''' (and the 118 multiple-model X-ray entries) should be the initial view in auto-seeded pages. Eric Martz plans to provide the script for this.
* '''Molprobity''' could be added under ''About this structure'' in the auto-seeded pages. Eric Martz plans to write a short explanation to accompany a link. [[User:Eric Martz|Eric Martz]] 20:00, 13 April 2008 (IDT)
* '''Sequence and structure-related''' entries could be linked to every entry. Currently, at [[2ic8]], I can click the link to PDBSum, and there click a mysterious plus button, which gives me a list of sequence-related entries. However, I must then enter each one by hand into Proteopedia. It would be great if this list, already linked, were at the bottom of every PDB-code-titled page. OCA already does sequence-based searching. All we need is a structure-based search as well for "structure neighbors". [[User:Eric Martz|Eric Martz]] 04:30, 26 April 2008 (IDT)
* '''SOLVED:''''' Green links are now bold by default.'' A user-settable preference to make all '''green links bold''' or underlined (when not touched with the mouse) (I prefer underlined, with bold onMouseover) because in Windows browsers, the font is very thin, and the green color is hard to see. It is hard to scan a paragraph and find the green links. Also 9% of males are colorblind. [[User:Emartz|Emartz]] 19:51, 9 March 2008 (IST)
* To encourage authors to follow [[Proteopedia:Policy]] regarding links to Wikipedia, automatically detect ''wikipedia'' during every preview/save and refer the author to [[Proteopedia:Policy]]. [[User:Emartz|Emartz]] 02:10, 16 March 2008 (IST)
* '''SOLVED:''''' When saving a scene (in the "save scene" dialog), a radio button to choose between "force '''spinning''' on", "force spinning off", "inherit spinning set by the user with 'toggle spinning'". (inherit spinning not implemented on purpose --[[User:Eran Hodis|Eran Hodis]] 22:23, 5 April 2008 (IDT))
* '''Tabulate characteristics''' of PDB codes on Category pages (in this order): PDB code, resolution, year, title, authors (ideally first and last author names like "Harel/Sussman" for 2ace), number of chains in the asymmetric unit, and ligand abbreviations. 2ace would look like this:
<table border=1 cellpadding=1><tr><td>
2ace</td><td>2.50A</td><td>1996</td><td>NATIVE ACETYLCHOLINESTERASE (E.C. 3.1.1.7) FROM TORPEDO CALIFORNICA</td><td> Harel/Sussman</td><td>Chains=1</td><td>ACH
</td></tr></table>
Topic pages should be listed first, before PDB code pages, and without any additional characteristics.

*'''SOLVED:''' Have selenomethionine (MSE) treated as any other amino acid in the (Jmol) default settings - [[User:Morten Grøftehauge]]- June 1, 2008. I agree that it is very strange to have MSE treated as a ligand! Fixing this is far more important than adding new display options, like 2 jmols, so I'm moving this up. - [[User:Kevin Karplus]] -18 Aug 2008. ''MSE'' and other [[Non-Standard_Residue]] are now properly identified in the Structure block. See [[2ab5]] - [[User:Jaime Prilusky|Jaime Prilusky]] 10:24, 19 August 2008 (IDT)

*'''SOLVED:''''' Mechanism to spawn (open) a '''child window containing only Jmol''' with the current scene. Advantages: the child window can be resized, thereby resizing Jmol; the child window can be kept in view while the text in the parent Proteopedia window is scrolled. It should be possible to have green links work on both the Jmol on the Proteopedia page, and the child Jmol. [[User:Emartz|Emartz]] 00:06, 17 March 2008 (IST). Implemented automatically generated button to spawn a popup window - [[User:Jaime Prilusky|Jaime Prilusky]] 10:16, 19 August 2008 (IDT)

* Automatically '''front, center, and size''' ligands and sites when their green links are clicked. That is, the molecule should rotate to put the selected entity in front of its center of mass, the selected entity should become the center of rotation/zoom, and the molecule should be zoomed (up or down) to make the selected entity fill e.g. 75% of the Jmol diameter.

* '''SOLVED:''' (March 2, 2008): Quality (antialiasing) chosen by the user with "toggle quality" should remain in effect for all green links within that page. Imagine that you're projecting scenes to a class. Currently, with every new scene, you have to click "toggle quality" again to get high quality.

* Support '''two Jmols side by side''', for comparisons. (''this is already possible, but not possible to sync them yet: see [[2b8n]]'' --[[User:Eran Hodis|Eran Hodis]] 22:23, 5 April 2008 (IDT))
** '''Synchronize''' mouse-directed rotations and zooms (this now works amazingly well, see Chapter 4 in the Demo Tutorial at http://bioinformatics.org/jmol-tutorials -- where by the way you can also see "toggle quality" working very clearly -- my links are labeled "smoother rotation" and "smoother graphics" to the lower left of Jmol).
** Provide a mechanism for '''one green link that sends separate scripts to each Jmol''' simultaneously. Maybe not necessary? Just use two green links? What is cool is to start with scenes that align the two molecules. Then they stay aligned as you rotate/zoom with the mouse (provided spin is left off at the beginning -- when it is on, one molecule tends to lag behind the other).
*Create a '''"reset" button for scene authoring tools''', in particular the representations tab. Or an "undo" button. Something to allow the image to be returned to normal after experimenting with different representations without reloading. [[User:Emily Forschler|Emily Forschler]] 00:07, 6 June 2008 (IDT)

* Add a 'quality' parameter to the applet tag to enable the quality level of the 3D model to be set on loading. [[User:Greg Black|Greg Black]] 21:41, 2 February 2009 (IST)

User:Greg Black/Sandbox 1

2009-02-02T15:13:24Z

Greg Black:

==The anti-cancer drug, cisplatin==

The discovery of the anti-cancer activity of cisplatin ([Pt(NH3)2Cl2] was serendipitous.

<applet load="1au5" size="300" color="white" frame="true" align="right" caption="Cisplatin" />

===Discovery===
Barnett Rosenberg, a physicist, thought that the picture of a cell dividing looked much like the pattern made by a dipole field with iron filings and a bar magnet, and he decided to investigate the cell division of the bacterium ''E. coli'' in the presence of a magnetic field. He found that cell division stopped but that the bacteria kept on growing, forming into long strands ref here. This effect had been caused by cisplatin, formed by the ammonium chloride nutrient, NH4Cl, reacting with the platinum electrodes under the effect of light and the electric field. The prevention of cell division is of course essential to cancer therapy. The next experiment was to inject doses of cisplatin into tumours in mice, and compare results against a control group: the tumours decreased dramatically in size. Medical research started immediately.

Dr Eve Wiltshore very rapidly showed that the drug had activity in ovarian cancer in particular and alongside that other trials showed that the drug was active in men with testicular cancer. Before the advent of cisplatin, in the case of men with testicular cancer the cure rate was something like 1 in 10; when cisplatin containing regimes came into clinical practice the cure rate went up to something like 9 in 10.

Cisplatin has side-effects, apart from nausea it can also cause kidney damage. It didn’t work against all cancers, and most of all there was a huge gap in understanding: how did it work, and why didn’t the ''trans-'' form of the same chemical have the same effect?

{{STRUCTURE_1au5 | PDB=1au5 | SCENE= }}

NMR proved to be an immensely useful tool in helping to determine both how cisplatin gets into the cells, and what happened to it once it was inside ref here. Cisplatin hydrolyses stepwise to produce positively charged ions. First, one chloride ion is replaced by water to form a species with a single positive charge and then the second chloride ion is replaced by a water molecule to an ion with two positive charges.

<scene name='User:Greg_Black/Sandbox_1/Platinum_orientation/1'>Test scene: cisplatin in the groove</scene>

pics here

When the Platinum complex becomes positively charged there would be a natural attraction for it to migrate to and bind to DNA which is a poly-anion. Cisplatin blocks the action of DNA - both replication and transcription.

Early NMR work ref here showed that most of the cisplatin formed what is called an adduct by linking to two neighbouring guanine bases on the same strand of the DNA through the N7 atom to form an intrastrand adduct.

pic here

More unusually, a very small amount of the cisplatin – less then 5% – bonded to the DNA so that the molecule actually straddled the two strands, making what is known as an interstrand adduct.

A major breakthrough came in the mid 1980s when Suzanne Sherman was successful in crystallizing the smallest building block on DNA bound to cisplatin ref here, and in 1995 Lippard’s group determined the crystal structure for the double stranded DNA complex that we see here.

Cisplatin is found to bind in the larger major groove. The platinum is still essentially square planar although the guanines are no longer parallel. The DNA molecule undergoes a significant bend, ranging from 50 to 80 degrees. Also the minor groove of the DNA substantially widens from the normal value in so-called B or classical B-form DNA of about 5 to 6 Ǻ up to 10 or 11 Ǻ. So opposite the cisplatin was a widened, flattened, minor groove. It seems to be this altered structure of DNA that leads to the recognition of other factors in the cell which ultimately produce the anti-cancer activity.

But there are also interstrand crosslinks that cross the two strands of DNA of which are maybe only 2 or so percent but there are a group of people who believe that they are the more important in terms of biological significance.

Proteins are the key to processes such as the repair mechanism. Normally, damaged DNA is recognised and marked for repair, which is done by cutting out the damage, so called excision repair. The bent platinated DNA seems to be recognised by other proteins – high mobility group, or HMG domains – which bind at the damaged site and prevent access by the repair proteins, protecting the adduct from excision repair. If this happened more efficiently in a tumour cell than in a normal cell of the same tissue that would be a wonderful mechanism for anti-cancer activity, and we're working hard to evaluate that hypothesis.

This structure shows an HMG protein – the red tube, attached to a natural binding site for transcription. It binds to the minor groove, but the similarity of the effect on the minor groove to the effect of cisplatin is striking. In both cases the minor groove becomes wider and shallower. Perhaps it is possible that the cisplatin DNA confuses the repair mechanism by this similarity and so escapes excision.

pic here – has this been proved?

===Carboplatin===
The problem with cisplatin was one of chemical reactivity – the rate at which those chloride ligands leave the molecule. And the whole idea behind carboplatin was to tone down that reactivity and in fact what is present in carboplatin instead of the chlorides is a cyclobutane dicarboxyato group which laboratory experiments have shown slows down the rate of aquation, the weight, the, the rate at which those ligands leave by about 10 fold in carboplatin and that has had a dramatic clinical effect in patients in that the kidney toxicity seen with cisplatin is almost totally absent with carboplatin and indeed the nausea and vomiting seen with cisplatin which is also a severe problem, is much less with carboplatin as well ref here.

User:Greg Black/Sandbox 1

2009-02-02T15:10:44Z

Greg Black: New page: ==The anti-cancer drug, cisplatin== The discovery of the anti-cancer activity of cisplatin ([Pt(NH3)2Cl2] was serendipitous. <applet load="1au5" size="300" color="...

==The anti-cancer drug, cisplatin==

The discovery of the anti-cancer activity of cisplatin ([Pt(NH3)2Cl2] was serendipitous.

<applet load="1au5" size="300" color="white" frame="true" align="right" caption="Cisplatin" />

===Discovery===
Barnett Rosenberg, a physicist, thought that the picture of a cell dividing looked much like the pattern made by a dipole field with iron filings and a bar magnet, and he decided to investigate the cell division of the bacterium ''E. coli'' in the presence of a magnetic field. He found that cell division stopped but that the bacteria kept on growing, forming into long strands ref here. This effect had been caused by cisplatin, formed by the ammonium chloride nutrient, NH4Cl, reacting with the platinum electrodes under the effect of light and the electric field. The prevention of cell division is of course essential to cancer therapy. The next experiment was to inject doses of cisplatin into tumours in mice, and compare results against a control group: the tumours decreased dramatically in size. Medical research started immediately.

Dr Eve Wiltshore very rapidly showed that the drug had activity in ovarian cancer in particular and alongside that other trials showed that the drug was active in men with testicular cancer. Before the advent of cisplatin, in the case of men with testicular cancer the cure rate was something like 1 in 10; when cisplatin containing regimes came into clinical practice the cure rate went up to something like 9 in 10.

Cisplatin has side-effects, apart from nausea it can also cause kidney damage. It didn’t work against all cancers, and most of all there was a huge gap in understanding: how did it work, and why didn’t the ''trans-'' form of the same chemical have the same effect?

{{STRUCTURE_1au5 | PDB=1au5 | SCENE= }}

NMR proved to be an immensely useful tool in helping to determine both how cisplatin gets into the cells, and what happened to it once it was inside ref here. Cisplatin hydrolyses stepwise to produce positively charged ions. First, one chloride ion is replaced by water to form a species with a single positive charge and then the second chloride ion is replaced by a water molecule to an ion with two positive charges.

<scene name='User:Greg_Black/Sandbox_1/Platinum_orientation/1'>Test scene: click here to zoom in on platinum</scene>

pics here

When the Platinum complex becomes positively charged there would be a natural attraction for it to migrate to and bind to DNA which is a poly-anion. Cisplatin blocks the action of DNA - both replication and transcription.

Early NMR work ref here showed that most of the cisplatin formed what is called an adduct by linking to two neighbouring guanine bases on the same strand of the DNA through the N7 atom to form an intrastrand adduct.

pic here

More unusually, a very small amount of the cisplatin – less then 5% – bonded to the DNA so that the molecule actually straddled the two strands, making what is known as an interstrand adduct.

A major breakthrough came in the mid 1980s when Suzanne Sherman was successful in crystallizing the smallest building block on DNA bound to cisplatin ref here, and in 1995 Lippard’s group determined the crystal structure for the double stranded DNA complex that we see here.

Cisplatin is found to bind in the larger major groove. The platinum is still essentially square planar although the guanines are no longer parallel. The DNA molecule undergoes a significant bend, ranging from 50 to 80 degrees. Also the minor groove of the DNA substantially widens from the normal value in so-called B or classical B-form DNA of about 5 to 6 Ǻ up to 10 or 11 Ǻ. So opposite the cisplatin was a widened, flattened, minor groove. It seems to be this altered structure of DNA that leads to the recognition of other factors in the cell which ultimately produce the anti-cancer activity.

But there are also interstrand crosslinks that cross the two strands of DNA of which are maybe only 2 or so percent but there are a group of people who believe that they are the more important in terms of biological significance.

Proteins are the key to processes such as the repair mechanism. Normally, damaged DNA is recognised and marked for repair, which is done by cutting out the damage, so called excision repair. The bent platinated DNA seems to be recognised by other proteins – high mobility group, or HMG domains – which bind at the damaged site and prevent access by the repair proteins, protecting the adduct from excision repair. If this happened more efficiently in a tumour cell than in a normal cell of the same tissue that would be a wonderful mechanism for anti-cancer activity, and we're working hard to evaluate that hypothesis.

This structure shows an HMG protein – the red tube, attached to a natural binding site for transcription. It binds to the minor groove, but the similarity of the effect on the minor groove to the effect of cisplatin is striking. In both cases the minor groove becomes wider and shallower. Perhaps it is possible that the cisplatin DNA confuses the repair mechanism by this similarity and so escapes excision.

pic here – has this been proved?

===Carboplatin===
The problem with cisplatin was one of chemical reactivity – the rate at which those chloride ligands leave the molecule. And the whole idea behind carboplatin was to tone down that reactivity and in fact what is present in carboplatin instead of the chlorides is a cyclobutane dicarboxyato group which laboratory experiments have shown slows down the rate of aquation, the weight, the, the rate at which those ligands leave by about 10 fold in carboplatin and that has had a dramatic clinical effect in patients in that the kidney toxicity seen with cisplatin is almost totally absent with carboplatin and indeed the nausea and vomiting seen with cisplatin which is also a severe problem, is much less with carboplatin as well ref here.

User:Greg Black

2009-02-02T12:24:58Z

Greg Black:

Dr Greg Black, Software developer, The Open University, Walton Hall, Milton Keynes, MK7 6AA UK.

[[User:Greg Black/Sandbox 1]]