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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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April 18, 2013

A Short Peptide And A Small Molecule

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Posted by Derek

Just as a quick example of how odd molecular recognition can be, have a look at this paper from Chemical Communications. It's not particularly remarkable, but it's a good example of what's possible. The authors used a commercial phage display library (this one, I think) to run about a billion different 12-mer peptides past the simple aromatic hydrocarbon naphthalene (immobilized on a surface via 2-napthylamine). The usual phage-library techniques (several rounds of infection into E. coli followed by more selectivity testing against bound naphthalene and against control surfaces with no ligand) gave a specific 12-mer peptide. It's HFTFPQQQPPRP, for those who'd like to make some. Note: I typo-ed that sequence the first time around, giving it only one phenylalanine, unhelpfully.

Now, an oligopeptide isn't the first thing you'd imagine being a selective binder to a simple aromatic hydrocarbon, but this one not only binds naphthalene, but it has good selectivity versus benzene (34-fold), while anthracene and pyrene weren't bound at all. From the sequence above, those of you who are peptide geeks will have already figured out roughly how it does it: the phenylalanines are pi-stacking, while the proline(s) make a beta-turn structure. Guessing that up front would still not have helped you sort through the possibilities, it's safe to say, since that still leaves you with quite a few.

But the starting phage library itself doesn't cover all that much diversity. Consider 20 amino acids at twelve positions: 4.096 times ten to the fifteenth. The commercial library covers less than one millionth of the possible oligopeptide space, and we're completely ignoring disulfide bridges. To apply the well-known description from the Hitchhiker's Guide to the Galaxy, chemical space is big. "Really big. You just won't believe how vastly, hugely, mindbogglingly big it is. . ."

Comments (18) + TrackBacks (0) | Category: Chemical Biology


1. marcello on April 18, 2013 12:38 PM writes...

Antibodies, baby!

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2. LUYSII on April 18, 2013 12:56 PM writes...

Yep, peptide/protein space is big all right. Even with phage display, assuming the phage has no mass at all, and assuming the entire mass of the earth is C, H, O, N and S in proper proportions, and making one molecule of each (e. g. 20 amino acids, 400 dipeptides, 8000 tripeptides etc. etc.) at what length of peptide/protein would you run out of material?

Make a guess, then have a look at

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3. gippgig on April 18, 2013 1:05 PM writes...

I haven't had a chance to look at the paper, but Fig. S4 in the supplementary information clearly shows that residue 4 is Phe not His, while 6-8 are Asn instead of Gln. It also shows residue 11 as some weird Arg analog with one N replaced by C and there are 2 N atoms in Pro 9!?

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4. gippgig on April 18, 2013 1:08 PM writes...

Oops, residues 6-8 are Gln. How'd I screw that up?

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5. Imaging guy on April 18, 2013 1:10 PM writes...

There are many antibodies which are claimed to bind to small molecules although I doubt their specificities. Abnova website lists more than 600 small molecule antibodies to be used with different methods of detection (e.g. ELISA, Western Blot, Radio and Enzyme immunoassays). Antibodies against GABA (PMID: 6587397), fluorescein, dinitrophenol and biotin can detect these molecules on fixed tissue sections. So it is not surprising that a peptide will bind to a small molecule.

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6. Mike on April 18, 2013 1:28 PM writes...

Derek, you had me confused for awhile, talking about pi-stacking phenylalanines when there is only one F in the peptide you describe. So for the record, the sequence is HFTFPQQQPPRP, not HFTHPQQQPPRP. :)

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7. leftscienceawhileago on April 18, 2013 1:44 PM writes...

Is there crystal structure in the paper by any chance (I don't have a subscription)? Generally hard to find aqueous structures for peptides that are that short...but given it is binding something I thought there might be a chance.

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8. Ed on April 18, 2013 2:29 PM writes...

2-naphthylamine is certainly an interesting choice - couldn't think of anything more carcinogenic?

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9. Curious Wavefunction on April 18, 2013 3:43 PM writes...

LUYSII: Yes, that calculation's well-known to people who do protein design (for instance Steve Mayo from Caltech has presented it in his talks). In spite of this combinatorial explosion of protein space, programs like Rosetta as well as methods like directed evolution can find peptides that bind with high affinity to almost any given target in a short time. It's the power of natural selection.

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11. dearieme on April 18, 2013 3:56 PM writes...

The Telegraph evidently found that story so interesting that it has a different version of the story too.

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12. luysii on April 18, 2013 4:13 PM writes...

#9: Curious Wavefundtion: What do Rosetta and methods like directed evolution start with? I really wish I had time to delve into this stuff more deeply, and will some day.

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13. barry on April 18, 2013 4:20 PM writes...

before we get to smug in our new knowledge of how these things work, remember that everyone was confident that choline receptors must have complementary charge to recognize the quaternary ammonium. In the event, the X-ray showed it's just a box of aromatic residues.
Not that choline is in any way drug-like or even lead-like. But it does mean that we mustn't think that a hydrophobic site on a target protein can only be satisfied by an un-drug-like grease blob.

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14. Imaging guy on April 18, 2013 4:45 PM writes...

# Curious Wavefunction
"programs like Rosetta as well as methods like directed evolution can find peptides that bind with high affinity to almost any given target in a short time"

Similar to you, many have claimed that antibody mimetics (peptides, affibodies, anticalins, designed ankyrin repeats and nucleic acid aptamers) against all known human proteins for detection, purification, imaging and therapeutic purposes will become available in near future. Still we are stuck with mono and polyclonal antibodies. What gives?

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15. RM on April 18, 2013 5:41 PM writes...

#12 luysii: Usually directed evolution starts with something that has a low level of desired activity, and through the process you gradually accumulate mutations that improve upon that activity. You can also start with completely random sequences (this is what the paper under discussion did, with random 12-mers). However, as mentioned, protein space is vast, and directed evolution isn't any better than random at going from a completely non-active item into an active item. For the first small bit of activity you have to get lucky.

Rosetta and the like do their screening in silico, so they can test more random combinations than most experimental platforms can. Additionally, they can theoretically rank the non-working items by how close they are to working. (e.g. telling the difference between +20 ddG and +10 ddG, whereas they're both "no signal" experimentally). You can theoretically start with a completely random peptide/protein, but the energy functions used don't match reality all that well, so in practice it's better to start with something that's close (e.g. something that already has the desired backbone conformation) and tweak it.

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16. Frank on April 18, 2013 6:15 PM writes...

I looked at the paper.
This is what we call non-specific binding in my lab.

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17. Crimso on April 18, 2013 7:04 PM writes...

"at what length of peptide/protein would you run out of material?"

I like to explain to my biochem students how to calculate the no. of possible 100 aa proteins (using the 20 standard aa). IIRC, it's very roughly Avogadro's no. times the estimated no. of atoms in the universe (give or take several orders of magnitude).

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18. sgcox on April 19, 2013 3:46 AM writes...

Agree with #16 Frank. Very slow SPR, no steady state and no saturation. This is normally called "atypical binder". You often see it with aggregation prone molecules. Not good.

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