Friday, October 28, 2005

Anti-freeze for winter weather

Winter is coming soon, my bike ride to work was pretty chilly, and it seems like a good time to be thinking about antifreeze. Antifreeze proteins, that is. Antifreeze proteins help keep pudgy yellow meal worms from turning into frozen wormsicles and artic flounder from becoming frozen flat fish.

Funny, but I would have thought that one antifreeze protein would be pretty much like another. I've played with some antifreeze structures before but I never realized that they're more diverse than you might guess. Some antifreeze proteins, like the one from the winter flounder and the sculpin are strictly alpha helical. Antifreeze proteins from yellow meal worms (aka "fish food") however, look pretty rigid and tough, with lots of organized beta sheets and a few random coils.

Who would have thought that two protein structures that seem so different would function in a similar way?

Or provide so much entertainment? I found lots of fun things to do with these structures while playing with them in Cn3D.

I noticed that the sequence of one of the structures contained an unusual amount of alanines (a's). I searched for alanines to highlight them in yellow. Which structure seems to be unusually high in alanines?

Coloring the structures by molecule, with the default rendering, shows some interesting yellow bars. Clicking the structure in the region of the bar, highlights a pair of c's in the sequence. Can you tell which structure contains disulfides?

Another question that springs to mind, in looking at the yellow meal worm protein, is this: what holds those two chains together? The two chains look like they're floating in space.

I know that the two chains aren't bound to each other by disulfides.

So, I asked if the two chains were associated by electrostatic interactions (bonds between positive and negatively charged amino acid side chains) by changing the coloring style to reflect charge. This color scheme shows negatively charged amino acids as red, positively charged amino acids as blue, and those with neutral side chains as grey.

You can download a key to the one letter abbreviations and a diagram of the amino acid structures from our web site:

So, are the two chains held together because of interactions between positive and negatively charged sidechains? What do you think the answer is?

I tried something else. I changed the rendering style to space fill and the coloring style to element.

oxygens are red,
nitrogens, blue;
sulfurs, are yellow (and so are you)

Ah there's nothing like good poetry (and that was nothing like it)

carbons are grey
and hydrogens are white.
I guess that makes everything quite alright.

We don't see hydrogens in X-ray crystal structures, though, since they're not heavy enough to scatter electrons.

Coming back to the two chains, it looks like the carbons fit together like a puzzle (remember, they're grey?).

I zoomed in for a better look.

The oxygens are lined up on the inside where the two chains interact. I think they might form hydrogen bonds, but remember, we generally can't see hydrogen bonds in crystal structures.

I guess it's time for NMR and a slice of rhubarb pie.


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Friday, October 21, 2005

Unusual biology on the internet

As a digital biologist, I spend way too much time on the Internet trying to postpone doing real work (just a joke, really!). One of my work-postponing occupations is reading about things like the Ig Nobel awards. The Ig Nobels reward science that makes you both laugh and think. These are great criteria for awards, since we scientists have a tendency to take ourselves far too seriously. Better yet, the Ig Nobels reward experiments that my kids would like. The award for biology went to researchers who actually smelled 131 species of frogs to see if the frogs were feeling stressed. My youngest child would love smelling frogs. Of course, I don't think we could do a good control experiment; all the handled frogs would be terribly stressed.

Others have already written about the award for medicine, which went to the inventor of Neuticles. These are fake testicles for dogs. Having known one male dog owner who refused to let his dog have the big operation, I think these are probably great for wives of male dog owners who sympathize with their dogs, just a bit too much.

But my favorite award from this year wasn't for biology. It was the literature award. The winners were those most creative e-mail writers, those enterprising Internet entrepreneurs and champions of persuasive communication, the Nigerian spammers. Some people enjoy their work so much they've gone to the trouble of collecting it and posting them for everyone to enjoy, see Scamorama.

Nothing like the continuing adventures from the Lads from Lagos and few sniffs of stressed frog to start the day off right.


Thursday, October 20, 2005

It all came out right in the end

Congratulations to Barry Marshall and Robin Warren for winning the 2005 Nobel prize in Physiology and Medicine for their discovery that Helicobacter pylori causes ulcers. I'm especially impressed with the experiment that Dr. Marshall carried out, drinking a solution of bacteria and giving himself ulcers. It makes me cringe but I'm glad he did it. The posting at the Nobel site has a nice description of the discovery.

Unfortunately, whenever I think about this or describe it someone, my brain insists on really bad jokes. My apologies to Barry Marshall, since there's nothing funny about his work. But ...

"It really took guts"

"He had intestinal fortitude"

"He had the stomach for the work"

"He swallowed the hypothesis, hook, line, and sinker"

"He put his whole self into his work" (or did he put his whole work into himself?)

"He felt in his gut that he must be right"

"He knew those weren't butterflies in his stomach"


Monday, October 17, 2005

Every structure has a story

It's been a long nitpicky journey but it's nearing the end. The almost-final version of the instructor manual, for "Exploring DNA Structure," has been sent off to the printer and there's nothing I can do now except patiently wait. In a week or so, I'll get to review it one more time in printed form and then release it to the world in November.

My family is quite relieved. For the past few week, I've been in distant space contemplating things yet to be done and obsessing about items that need to get checked off the list. It's gotten so bad that I spend soccer games thinking about margin size or I take the dog for a walk and stop suddenly to tell my husband that I must check the index one last time and make sure that all that chapters are starting on the right side of the page.

It's all worth it, though. I confess I've become totally entranced with molecular structures. They are the most fascinating art form I've ever seen and every structure has its own story. I know because I read and wrote 69 structure stories for the "Exploring DNA Structure" instructor guide. This was never in my original plan but my friend Charlotte Mulvihill wrote to ask me about the functions of different structures. I blithely replied that sometimes the only function was to satisfy the curiosity of the researchers. Then, I started to wonder, too, and couldn't help reading about all of them and compiling an answer guide for the manual.

The more I learned, the more fascinated I became. Some of my favorites are shown below.

Many structures on the CD contain anti-cancer or antiviral drugs bound to DNA. These drugs kill cancer cells by making it hard for cells to copy, unwind, or repair their DNA. Although these drugs harm all growing cells, cancer cells suffer the most damge since they grow more rapidly than normal cells. This image shows tamoxifen, a drug used to treat breast cancer, bound to DNA.

Telomeres protect the ends of linear, eucaryotic chromosomes. Unlike the rest of the chromosome, with double-stranded or duplex DNA, telomeres form four-stranded quadruplex structures with lots of positively charged ions. I think the ions probably shield the negatively charged phosphates and allow the strands to get close together.

DNA can form interesting loop structures where a single-strand kind of twists around back on itself. This structure is thought to regulate expression of the protective antigen gene, in Bacillus anthracis, the bacteria that cause antrax. The protective antigen plays a key role in development of anthrax symptoms. If we can understand how this gene is turned on or off, perhaps we can find a way to turn this gene off and prevent the symptoms altogether.

Recombination intermediates, also known as Holliday structures, are wild. When I was an undergraduate, I found recombination to be very mysterious. This structure shows DNA in the act of breaking and joining to other strands. Seeing the structures makes genetics less mysterious and considerably more fun.


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