Feng Zhang's CRISPR "Miami Moment"

I've spent a bit of time this week trying to grok the ever-expanding frontier where biology meets chemistry. RNA therapeutics, chemical probes, synthetic biology, protein engineering...I could go on and on. Of course, this list would be woefully incomplete without the new cool kid: CRISPR.

If you've read a few of the stories surrounding this field's origins, you'll recognize the names Doudna, Charpentier, and Zhang. An interesting story arc emerges in the countless biographies surrounding Feng Zhang, now at MIT / Broad. Here, it's retold through the lens of WIRED author Amy Maxmen:

"Soon after starting [at the Broad], he heard a speaker at a scientific advisory board meeting mention Crispr. 'I was bored,' Zhang says, 'so as the researcher spoke, I just Googled it.' Then he went to Miami for an epigenetics conference, but he hardly left his hotel room. Instead, Zhang spent his time reading papers on Crispr and filling his notebook with sketches on ways to get Crispr and Cas9 into the human genome. “That was an extremely exciting weekend,” he says, smiling."

Have you ever had a point in your life like this?  Perhaps Zhang truly found the conference boring, and researching CRISPR was his best escape. However, since this story crops up so often, I'd like to think it's an attempt to capture the "flow" state as it applies to crystallization of a new field of research or career direction. Hopefully you recognize the feeling - total immersion, loss of time, tuning out all external concerns while your brain opens up to the vast possibilities of something truly new.

Clearly, a computer algorithm with a scientific sense of humor printed this lotto ticket. 

From my own experience, I can remember a handful of flow moments that I sustained for longer than a few hours. In the first, I spent two or three days reading everything I could about a competitor's catalysis research - hoping not to get scooped - and encountering multiple exciting ideas about monodentate ligand binding left unexplored. In another, I tried to track the entire Vinca metabolism from Tryp to the few hundred polycyclic alkaloids like vincristine and ajmaline. Plant metabolism turns out to be much more complex than I'd ever imagined.

Readers, I'm certainly not alone...can you recall when you've experienced a version of Feng's Miami moment? What was it like?

Lord of the (Small) Rings

Quick: What small, odd-looking thing carries metal through harsh trials?

Here's hoping you answered the Doyle group's new ligand: "Fro-DO."

I see what you did there.
Credit: Doyle group, JACS 2015

Unlike common sigma donors - NHCs, amines, phosphorous ligands - EDO (electron-deficient olefin) ligands function as pi-acceptors. Instead of dumping electron density into oxidative addition (adding an R-X bond across a metal atom) EDOs speed up* the other side of  catalysis, namely reductive elimination (joining the organic fragments and restoring the metal's electrons). According to the authors, acceleration of reductive elimination helps to decrease the amount of substrate decomposition due to beta-hydride elimination.

Doyle and coworker Dennis Huang report selective ring-opening of aziridines - no mean feat in itself -  and generate a quaternary center in the process, in 31-86% yields. Using a modified camphor-like sultam for their EDO, the group observes 27% ee, sure to be the focus of its own publication in the near future. Curious about related efforts in other groups? I recommend this Jamison mini-review.

Now, back to the name: "Fro-DO" carries the torch for a small-but-growing literature subculture. Chalk up another example to what The Atlantic recently called "Science's Love Affair with LOTR." I spent a few moments with SciFinder, trying to dig up some more chemistry-themed examples; the Atlantic points out many from geology and astronomy, and precious few from our molecular audience. Without further ado:

• Superconducting magnets used in fusion research, controlled by codes nicknamed SARUMAN and GANDALF

• Retrotransposons in a .small flowering plant, dubbed "Gimli," "Gloin," and "Legolas"

• A breast cancer gene marker, called "Frodo"

• MRI pulse sequences, used to eliminate artifacts, also dubbed "FRODO"

• Finally, a docking program for small molecules and RNA, with an apt name: "MORDOR"

Readers, any more chemistry-themed LOTR callbacks? Send 'em along!

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*...or maybe not. An observant commenter on Reddit noticed that Doyle and colleagues see no correlation between 13C shift of the olefinic EDO carbons and reaction rate. They posit, instead, substantial steric congestion around the metal surface as responsible for the rate enhancement.

Review: ChemBioDraw 14.0

Dear ChemBioDraw* Ultra 13.0,

Listen, we had a good run together. But I've fallen for another: ChemBioDraw Ultra 14.

My good friends at PerkinElmer (PKI) were kind enough to grant me trial access to their spiffy new chemistry drawing software. As an avid user since, oh, say, ChemDraw Pro 4.5, I feel confident in stating that this version wins all around for smoother operation, better templates, easier file export, and better shortcut keys.

So, I figured what PKI really wanted me to do most was to try and BREAK ChemBioDraw 14.0
 . . .if I could. Did I succeed? Let's talk a walk through the software and find out.

CBD 14.0 means NEVER seeing this screen again (hooray!)

Starting at the top, I figured I'd check the "What's New?" link in the help menu. One thing I appreciated more than I thought? ChemBioDraw 14.0 directing "Help" queries into the appropriate section of the User Guide. Version 13 still spawned its help window inside Windows help, with the infamous purple booklets leading you down wild goose chases of clunkily-presented information.

Drawing hasn't changed much since 13.0. At least the text direction auto-correct -- which drove me batty in former iterations -- seems to have been tweaked; the system now opens my older drawings the way I typed 'em in originally (hence, below, attaching pasta sauce to a scaffold in place of a sugary placeholder).

I promise this made sense in earlier ChemDraw versions...

The CBD 14.0-to-SciFinder jump works much more smoothly than I had anticipated. For those of us who shuddered through dial-up desktop versions of SciFinder in the late '90s, this version feels like the sleek Lamborghini of the search world. After drawing (or importing) my structures of choice, I lassoed them up and pressed the little "SciFinder diamond" on the top toolbar. Within about 5 seconds, a new window opened with the standard exact / substructure motif. Two clicks later, I'd be deep into the primary literature.

So, my goal was to break the system, right? Here's a logical place to try - I attempted to load each and every complex structure I had drawn since starting my fledgling blogger's career, around 2009 or thereabouts. Again, I was amazed by the speed and accuracy of the SciFinder pop-out, which returned roughly 90% of the correct molecules I'd searched for (below):

From this 2011 post

From this 2013 post

From this 2014 post

However, it's not all bubbles and sunshine. Two of my molecular queries bore no fruit**; perhaps they're too new to have been uploaded into CAS's databases yet. But one thing remains tricky: drawing and searching for metallocenes. Along with their new push into biology clip art, ChemBioDraw has a renewed focus on making sure you've got those sandwich compounds properly aligned.

Sigh. If only I remembered what they were all supposed to be...

Now, even after aligning my query using the proper template, SciFinder makes a mess out of it.

From this 2012 post

So, obviously I went looking for things to break, and found some rather limited examples. Honestly? The rest of the program works pretty well. And writing this review gave me a wonderful opportunity to poke and prod at the product in ways I hadn't in far too long.*** I finally realized you could change the solvent on the NMR predictor! I played around with expanding and collapsing peptide and RNA strings. And the post-drawing mods to more complex peptides, like disulfide and lactam cross-linking? Much better.

Found on p. 126 of the User Guide. (Get it?)
I'd like to shake the hand of the person who slipped this in...

R.I.P., Optimizing Octopus

I will take this final moment to remember a long-lost piece of ChemDraw lore. Once upon a time, to "clean up" one's structures, the icon looked something like this (right). I've heard it referred to as a jellyfish, a squid, a broom (no!), but I always knew it as a friendly little octopus. With CBD 14, any doubt about its brushiness has been cast aside with a full-out icon redesign.


Looks great, guys. Now let me think about more ways to use it for actual work!

Thanks again to Philip Skinner and PerkinElmer for the chance to review the software.

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*For other blog reviews of ChemDraw products, see Jess The Chemist, Andre the Chemist (no relation), or Chemjobber.

**Here's the structures that returned empty SciFinder searches. Both compounds (left, right) were first reported in 2014.

***P.S. I never knew you openly solicited beta testers for these products...gimme a call sometime, PKI!