[crystalguy]

Cystine is poorly soluble in water.  It is essentially two Cysteine amino acids linked through their side chains by a thioether. 

I would like to ask how Cystine can be made more water soluble without drastically modifying its structure.  Eg. Can the sulfur atoms in the thioether link be replaced by another atom that would have a similar chemistry and size but make it more soluble in water? 

What about addition of more polar moieties to either the amino or carboxy ends of the individual amino acids. I would have thought that at around neutral pH since both the amino and carboxy are ionized (i.e. zwitterionic form) that they would be sufficient to make Cystine as a whole, more soluble in water, but apparently not. So what minor changes could be made here to make Cystine more water soluble?

Thanks in advance for any suggestions.

[wildfyr]

If you modify the atoms On cystine it is no longer cystine.

In such a small bioactive molecule, any change will have strong effects on function.

Cysteine can be reduced to two cystines for better solubility and they won't rejoin immediately.

[crystalguy]

If you modify the atoms On cystine it is no longer cystine.

In such a small bioactive molecule, any change will have strong effects on function.

Cysteine can be reduced to two cystines for better solubility and they won't rejoin immediately.

I don't need it to be exactly Cystine, just to mimic it, for example as is done in so many drugs where they mimic protein substrates but are unreactive. A more specific example, phosphoserine can be mimicked with the amino acid glutamic acid - not exactly, but the size and charge are similar.

Can't use Cysteine, because the it won't bind, need a Cystine mimic. Any ideas for modification that can be made that will retain similar properties (not exactly of course) but is more soluble.

[crystalguy]

I suppose I'm looking for advice from chemistry experts that can offer insight into what chemical modifications are feasible to make.

For example, what about linking Serine amino acids by their side chain via the link (-O-O-) like (-S-S-) in Cystine.  Is this chemically feasible? 

[vikram]

If you are searching for similar structure with water solubility, then Serine would be one of the choice.-SH is replaced by -OH

[Babcock_Hall]

crystalguy,

If you link two serine atoms in the way that you suggest, it would create a peroxide functional group, which has certain chemical properties that might be undesirable in your application.  Also, the bond lengths and bond angles would not be identical.

[rolnor]

A sulphur atom can be replaced by two methylene groups, you can replace the S-S link with CH2CH2CH2CH2. I would be interesting to look at this in a molecular modeling software.
Maybe its better with three methylenes, CH2CH2CH2.
If this gets you better solubility is not certain.

[crystalguy]

If you are searching for similar structure with water solubility, then Serine would be one of the choice.-SH is replaced by -OH

the only problem is that it needs to be in the context of Cystine, i.e. -O-O- vs. -S-S-, not -OH vs. -SH

[crystalguy]

A sulphur atom can be replaced by two methylene groups, you can replace the S-S link with CH2CH2CH2CH2. I would be interesting to look at this in a molecular modeling software.
Maybe its better with three methylenes, CH2CH2CH2.
If this gets you better solubility is not certain.

That seems like a good idea, but unfortunately, I doubt -CH2- groups would improve the solubility.

[wildfyr]

What is the desired usage?

[crystalguy]

What is the desired usage?

To have it act as a substrate mimic for a protein it binds to.

[hypervalent_iodine]

What is the desired usage?

To have it act as a substrate mimic for a protein it binds to.

Do you know exactly how it binds to this protein? What you are looking for is a bioisosteric replacement, but it is difficult to be able to suggest one without knowing more information, since bioisosteres are heavily context-dependant.

Is the cysteine part of a larger molecule? Is the intended application for use in some sort of medicine? Why is it important that it be very water soluble?

[crystalguy]

What is the desired usage?

To have it act as a substrate mimic for a protein it binds to.

Do you know exactly how it binds to this protein? What you are looking for is a bioisosteric replacement, but it is difficult to be able to suggest one without knowing more information, since bioisosteres are heavily context-dependant.

Is the cysteine part of a larger molecule? Is the intended application for use in some sort of medicine? Why is it important that it be very water soluble?

No clue how it binds.  The protein is a channel that actually transports cystine across a membrane.  The Cystine is standalone, it's the result of degradation of disulphide bond containing proteins.  The intended application is to study the binding of Cystine in complex with the protein to get an idea of where and how it binds. The solubility needs to be improved because we need to add large quantities to small volumes, and presumably its binding affinity is quite weak. Having an improved solubility Cystine mimic, we can just throw in loads of it to drive the binding without it precipitating out of solution.

[hypervalent_iodine]

What is the desired usage?

To have it act as a substrate mimic for a protein it binds to.

Do you know exactly how it binds to this protein? What you are looking for is a bioisosteric replacement, but it is difficult to be able to suggest one without knowing more information, since bioisosteres are heavily context-dependant.

Is the cysteine part of a larger molecule? Is the intended application for use in some sort of medicine? Why is it important that it be very water soluble?

No clue how it binds.  The protein is a channel that actually transports cystine across a membrane.  The Cystine is standalone, it's the result of degradation of disulphide bond containing proteins.  The intended application is to study the binding of Cystine in complex with the protein to get an idea of where and how it binds. The solubility needs to be improved because we need to add large quantities to small volumes, and presumably its binding affinity is quite weak. Having an improved solubility Cystine mimic, we can just throw in loads of it to drive the binding without it precipitating out of solution.

In that case, I would say that you are stuck using cysteine. As was mentioned above, any molecular changes you could make to it would render it no longer cysteine, and using such a molecules to make conclusions about how cysteine bonds would be a bit dodgy, IMO.

What method are you using for co-crystallisation? If you use the hanging drop method, there’s no reason you couldn’t dissolve the cysteine in DMSO. There are also other ways to acoustically shoot molecules into crystals that may be of assistance.

[crystalguy]

What is the desired usage?

To have it act as a substrate mimic for a protein it binds to.

Do you know exactly how it binds to this protein? What you are looking for is a bioisosteric replacement, but it is difficult to be able to suggest one without knowing more information, since bioisosteres are heavily context-dependant.

Is the cysteine part of a larger molecule? Is the intended application for use in some sort of medicine? Why is it important that it be very water soluble?

No clue how it binds.  The protein is a channel that actually transports cystine across a membrane.  The Cystine is standalone, it's the result of degradation of disulphide bond containing proteins.  The intended application is to study the binding of Cystine in complex with the protein to get an idea of where and how it binds. The solubility needs to be improved because we need to add large quantities to small volumes, and presumably its binding affinity is quite weak. Having an improved solubility Cystine mimic, we can just throw in loads of it to drive the binding without it precipitating out of solution.

In that case, I would say that you are stuck using cysteine. As was mentioned above, any molecular changes you could make to it would render it no longer cysteine, and using such a molecules to make conclusions about how cysteine bonds would be a bit dodgy, IMO.

What method are you using for co-crystallisation? If you use the hanging drop method, there’s no reason you couldn’t dissolve the cysteine in DMSO. There are also other ways to acoustically shoot molecules into crystals that may be of assistance.

The protein won't bind Cysteine, it does not transport cysteine.  It only transports Cystine.  Actually getting a small molecule mimic is more than just trying to understand where and how it binds, it's to stabilize the protein as well to coax it to crystallize - this is very commonly done.

Yes hanging drop.  Can't use DMSO, too much of it will cause the protein to unfold.  Maybe can get away with less than 1% DMSO, but that won't dissolve Cystine.