Heme Groups

 
Monday's Molecule #37 is the heme group found in myoglobin and hemoglobin. The heme group consists of a ring structure, called a tetrapyrrole ring system, complexed to a central iron atom. There are many different kinds of these tetrapyrrole structures in cells. They are distinguished by slight changes in the chemistry of the ring system. This particular structure (left) is called protoporphyrin IX. The structure was originally determined by Hans Fischer [Nobel Laureate: Hans Fischer],

The red color of blood is due to the presence of the heme group, which absorbs visible light. Note that the pyrrole rings are linked by methene bridges (-CH=) to create a conjugated double bond system where electrons can be shared all across the ring. Not only does this mean that these rings can absorb photons, it also means that they can accommodate additional electrons without too much trouble.

This is why there are many heme proteins that are involved in oxidation-reduction reactions (reactions that transfer electrons from one substrate to another). For example, cytochrome c has a similar kind of heme group (right). Cytochrome c is a major player in membrane associated electron transport systems in bacteria and mitochondria and in photosynthesis.

Heme type molecules are always tightly bound to proteins. Such molecules are called prosthetic groups and there are two types. The heme in hemoglobin is bound by many weak interactions such as hydrogen bonds and van der Waals interactions. The heme in cytochrome c is an example of a covalently bound prosthetic group. It is attached to its protein by bonds between the edge of the porphyrin ring and cysteine (Cys) side chains in the protein.

Chlorophyll (left) is another type of tetrapyrrole ring molecule but it differs from most others because the central chelated metal ion is magnesium (Mg) instead of iron. Chlorophyll molecules absorb light very efficiently and that's why they play such an important role in photosynthesis. Photosynthesizing organisms—bacteria, algae, plants—have dozens (or hundreds) of chlorohyll molecules packed in their membranes.


©Laurence A. Moran and Pearson Prentice Hall 2007

Physicians Are "Science Professionals"

 
At least that's what the IDiots say [Medical Doctors a Fast Growing Segment of Darwin Doubting Science Professionals].

Who knew? I suppose we shouldn't be surprised if they think an M.D. degree makes you a "science professional." After all, these are some of the same people who think the Earth is only 10,000 years old.

UPDATE: Turns out that many of these medical doctors are actually dentists [Dentists Against Darwin]. Sheesh!

Your View of Evolution

 
The poll for August asks you to identify the person who comes closest to representing your view of evolution. Check out the left hand margin.

70% of Sandwalk Readers are Atheists

 
According to the latest poll (see left hand margin) 70% of Sandwalk readers are atheists (PZ would be proud.). 12% are agnostics—I guess Wilkins and Catshark figured out how to vote multiple times. Only 14% are believers. I wish there were more believers, it would make for more lively discussions.

Six of you are uncertain. Why?

Another Bad Review of The Edge of Evolution

PZ Myers draws attention to another review of Michael Behe's new book The Edge of Evolution [Behe gets another thumbs-down]. This review is published in the July issue Discover magazine [The Simplistic Manifesto]. The author is Cory S. Powell.

I disagree with PZ. This is not a good review. Actually, it's a very bad review. Like many of the published reviews of The Edge of Evolution the author seems to have been reading a far different book than the one I read. Powell says,

To reach this conclusion, Behe makes a number of invalid assumptions about how molecules evolve and interact. He alleges that, because many functional adaptations require multiple changes in proteins, two or more mutations must occur together at the same time in the same gene and only rarely can several mutations "sequentially add to each other to improve an organism’s chances of survival." But in fact natural selection does work on transitional forms, as molecules and traits evolve stepwise. Stepwise evolution has been well documented; one good instance of this is the emergence of color vision. Mutations add up little by little, leading to major changes to proteins over time.

The essence of Behe's argument is not that it's impossible to evolve a double mutation if each one is beneficial. The whole point of the book is that stepwise evolution requires that each step is beneficial. The evidence, according to Behe, shows that many cases involving double mutations involve intermediates that are disadvantagous. Thus, the double mutant had to arise in a single step and this is highly unlikely.

Behe isn't always as clear as he should be but he does make it perfectly clear that he accepts the mechanism that Powell describes. Thus, Powells' criticism is inappropriate and this makes it a bad review. Apparently Powell didn't read the section on the evolution of antifreeze proteins in fish (pp. 77-81) where Behe describes each of the many steps that lead to the modern antifreeze proteins.

Each step would have given the fish some protection against freezing water. Thus, Behe concludes,

Even though we haven't directly observed it, the scenario seems pretty convincing as an example of Darwinian evolution by natural selection. It's convincing because each of the steps is tiny&mdash'no bigger than the step that yielded the sickle cell mutation n humans—and each step is an improvement.

The Discovery review points out that complex combinations of mutations can arise in a stepwise manner by standard Darwinian mechanisms. It implies that Behe never thought of this in his book but that's total nonsense. Of course he did. Behe doesn't deny that phenotypes requiring multiple steps can be produced by random mutations, as long as each step is beneficial. The essence of his argument is that it's impossible to generate phenotypes that require multiple random mutations if the intermediates aren't beneficial.

I'm not arguing that Behe is correct. In fact, I'm preparing a series of postings that will challenge some of his ideas. What I'm objecting to is the mischaracterization of Behe's arguments in many of the published reviews. If you're going to criticize Behe then challenge the argument he makes in the book; namely, that most stepwise pathways are impossible because the intermediates are less fit than their parents.

Powell makes another common mistake in his review. He says,

Behe makes another big, related error in the way he interprets how proteins work together. He contends that for even three proteins to evolve in a cooperative association is wildly improbable, "beyond the edge of evolution." Within a protein, five or six amino acids (components of proteins) need to change simultaneously for it to bond with another protein, according to Behe. From this he concludes that it is impossible for proteins’ interaction to evolve, again requiring life to have been programmed for success from the start. Plenty of evidence contradicts this assertion, however. Many proteins within cells interact with other proteins in ways in which only two or three amino acids are critical for binding.

Behe admits that you may only need three or four selected changes in order to generate a new binding site (p. 114). He agrees that the evolution of a single binding site is within reach of evolution but the simultaneous generation of two binding sites is beyond the edge of evolution because the probabilities are so low. The point is that there are many complexes that require the interaction of several different proteins and the intermediates—where only two proteins interact—are not beneficial. Refuting Behe's real arguments requires a little more effort than the superficial criticism of arguments that Behe is not making.

Powell continues,

Such simple binding sites can arise frequently in proteins. And such interactions form the networks that regulate all sorts of physiological processes in cells and organisms. Cell biologists and biochemists are increasingly finding that, in truth, protein interactions and networks are easy to evolve. Behe should know this—but he has a long history of alleging evolutionary impossibilities and ignoring the scientific literature.

Powell is completely missing the point here. Behe does not deny that such complexes exist, nor does he deny that they evolved in the sense that they arose in organisms whose ancestors didn't have them. Once the mutations occurred, they became fixed in the population by natural selection. Furthermore, Behe does not deny that these networks are "easy to evolve." In fact, they are so "easy to evolve" that they cannot be explained by natural selection acting on random mutations as "Darwinism" requires. Thus, mutations cannot be random.

You don't refute Behe by pointing to examples of evolution by common descent or natural selection; this includes evolution of protein complexes. That's not the point. The point is that "Darwinian" evolution, according to Behe, must require small steps where each step is beneficial and this cannot be demonstrated. Indeed, in many cases the intermediates will likely be detrimental. The conclusion is that multiple mutations have to occur simultaneously as in some drug resistance. For most populations the probability of this happening by random mutation is very small. The fact that it happened is evidence of directed mutation, or so Behe thinks.

In order to show that Behe is wrong you have to demonstrate that his understanding of evolution (i.e., "Darwinism") is wrong and this has led him to false conclusions about probabilities. Many reviewers have failed to do this, possibly because they accept Behe's version of Darwinism.

You can read Michael Behe's responses to his reviewers on the Amazon.com site [Michael Behe's Amazon Blog]. I think it's fair to say that Behe makes some good points (and many bad ones) when he accuses his reviewers of misrepresentation.

Virtual Toronto

 
Here's a site that combines an interactive map of Toronto with images from selected streets [Toronto Virtual City]. The photograph (left) shows the entrance to my building on the University of Toronto campus. The view is looking north from College St.

The satellite view is about two years old. It was taken when the new building was still under construction so the street level image doesn't match the satellite view.

Hmmm ... that reminds me. How come we don't see any more postings where we have to identify a university campus? I forgot which blog that was on.

[Hat Tip: Monado]

Gene Genie #12

 


Gene Genie #12 has been posted at My Biotech Life [Gene Genie #12 aka The Dozen].

The image is from the article on snpedia [WikiPedia Meets Genetics]. Read about how you can access the personal genome of Jim Watson and Craig Ventor.

Monday's Molecule #37

 
Today's molecule looks complicated but it has a very simple name. The short common name of this molecule is not sufficient—you have to supply the correct biochemical name that distinguishes this molecule from similar ones found inside all cells. You're more than welcome to supply the complete IUPAC name if you know it.

There's an indirect connection between this Monday's Molecule and Wednesday's Nobel Laureate(s).

The reward (free lunch) goes to the person who correctly identifies the molecule and the Nobel Laureate(s). Previous free lunch winners are ineligible for one month from the time they first collected the prize. There's only one (Marc) ineligible candidates for this Wednesday's reward since many recent winners haven't collected their prize. The prize is a free lunch at the Faculty Club.

Comments will be blocked for 24 hours. Comments are now open.

Canadian Dinosaur Coins

 
The Royal Canadian Mint has dinosaur coins for sale. Here's a picture of the first one. It shows a fossil Parasaurolophus, a crested, duck-billed species from Alberta.

Future coins will depict Triceratops (2009); Tyrannosaurus rex (2009); and Dromaeosaurus (2010). The face value of the coins is $4 (CDN)—that's currently about $3.80 in US currency but it will be about $4.60 by the time the last coin is issued unless the US dollar stops falling. (Getting out of Iraq would help.)

Only 20,000 coins are being minted. The finish on the "fossil" image is impossible to reproduce exactly so each coin will be slightly different in tone and color. You can buy them for $39.95 (CDN).

How many people know what "D.G. Regina" stands for? (Hint: it's not an atheist slogan.)

The OUT Campaign

 
RichardDawkin.net has started something called the The OUT Campaign. The goal is to encourage all non-believers (atheists) to come out of the closet and make their rejection of religious superstition known. You're supposed to use the red "A" as a symbol to declare that you are an atheist. Several bloggers have put it on their website.

I do not believe in God. I am an atheist. However, the fact that I don't believe in something is often the only thing I have in common with other atheists. It seems a bit silly to form a club based only on what you don't believe in. It would be like having a club for everyone who doesn't believe in Bigfoot, or Santa Claus.

So, while I am happy to announce my preference for rationalism over superstition and proud to be an atheist. I won't be joining any organization based on a negative. I am a proud member of Skeptics Canada and The Centre for Inquiry, Toronto because they stand for something positive.

[Hat Tip: PZ Myers]

The Aliens Are Coming

 
Friday's Urban Legend: False

			The following email message is going the rounds. ALIENS ARE COMING TO ABDUCT ALL THE GOOD LOOKING AND SEXY PEOPLE. YOU WILL BE SAFE, I'M JUST EMAILING TO SAY GOODBYE. We know it's false because I'm still here.

Theme: Deoxyribonucleic Acid (DNA)

 
THEME

Deoxyribonucleic Acid (DNA)

1. Wellcome Trust Images


2. A Strange Molecule


3. Monday's Molecule #35 (ethidium)


4. DNA Is a Polynucleotide


5. Tautomers of Adenine, Cytosine, Guanine, and Thymine


6. Nucleotides Can Adopt Many Different Conformations


7. Nobel Laureates: Francis Crick, James Watson, and Maurice Wilkins


8. The Chemical Structure of Double-Stranded DNA


9. The Three-Dimensional Structure of DNA


10. The Story of DNA (Part 1) Where Rosalind Franklin Teaches Jim and Francis Something about Basic Chemistry


11. Ethidium Bromide Binds to DNA


12. Rosalind Franklin Announces the Death of the Helix


13. Nobel Laureates 1962


14. The Story of DNA (Part 2)Where Jim and Francis Discover the Secret of Life


15. DNA With Parallel Strands


16. Measuring Stacking Interactions


17. Are You as Smart as a Third Year University Student?


18. Rosalind Franklin's Birthday


19. The Watson & Crick Nature Paper (1953)


20. The Franklin & Gosling Nature Paper (1953)


21. The Wilkins, Stokes and Wilson Nature paper (1953)


22. Ethidium Bromide Is a Dangerous Chemical


23. Jim Watson on the Discovery of the Double Helix


24. DNA Tatoo


25. DNA Polymerase I and the Synthesis of Okazaki Fragments


26. Play the DNA Double Helix Game

The Wilkins, Stokes and Wilson Nature paper (1953)

Wilkins published his work on the structure of DNA in the same issue of Nature as the Watson & Crick paper and the Franklin & Gosling paper. The coauthors on the wilkins paper were A.R. Stokes and H.R. Wilson. They were reunited in 1993 on the 40th anniversary of the publication as shown in the photo. (From left to right: Raymond Gosling, Herbert Wilson, Maurice Wilkins and Alec Stokes.)

A copy of the Wilkins, Stokes and Wilson paper is here.

The title of the paper "Molecular Structure of Deoxypentose Nucleic Acids" indicates that this is a paper that will discuss details and experimental results. This is a paper that emphasizes the similarities between X-ray diffraction patterns of DNA fibres from calf thymus, wheat germ, herring sperm, human, and T₂ bacteriophage. They also look at DNA in vivo by examining intact sperm heads, bacteriophage, and animal viruses. The authors conclude that all these DNA have the same general structure and that it is consistent with the model proposed by Watson & Crick.

The Franklin & Gosling Nature paper (1953)

Rosalind Franklin and Raymond Gosling published their results on the structure of DNA in a Nature paper that immediately followed the famous Watson & Crick paper [The Watson & Crick Nature Paper (1953)]. Franklin had completed the manuscript before traveling up to Cambridge to see the Watson & Crick model of DNA but she was able to make changes to her paper before submitting it in early April 1953. A PDF of the paper as it appeared in the journal is here and the original manuscript is here.

The title of the paper, "Molecular Configuration in Sodium Thymonucleate," gives us a clue to why this paper has been ignored and the Watson & Crick paper gets all the attention. The Franklin & Gosling paper is full of obscure references and equations and it's significance can only be recognized because of the paper that preceded it in the April 25th, 1953 issue of Nature. The writing style is ponderous and it does not convey any of the sense of excitement found in the Watson & Crick paper [see April 25, 1953: Three papers, three Lessons].

Franklin and Gosling conclude that DNA is "probably helical," the phosphate groups lie on the outside, and there are probably two strands. They state,

Thus our general ideas are not inconsistent with the model proposed by Watson and Crick in the preceding communication.

As is the case in the Watson & Crick paper, papers in the same issue of the journal are not specifically referenced. If you follow the link to the typed manuscript (above) you can see that this sentence was inserted by hand.

Franklin & Gosling acknowledge their colleagues at the end of the paper in the same manner we saw in the Watson & Crick paper.

We are grateful to Prof. J.T. Randall for his interest and to Drs. F.H.C. Crick, A.R. Stokes, and M.H.F. Wilkins for discussion.

The Watson & Crick Nature Paper (1953)

Watson & Crick submitted their paper on the structure of DNA to the journal Nature on April 2, 1953. It was published in the April 25th issue—a remarkably rapid publication even for that time. A PDF of the paper as it appeared in the journal is here. The original typed manuscript is here.

Now that we've learned about the structure of DNA and it's history [Theme: DNA] we're in a position to work through this seminal paper line-by-line. Let's begin with the title and the opening sentence.

A Structure for Deoxyribose Nucleic Acid

We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.

The name of this important molecule is now deoxyribonucleic acid but in 1953 there was no standard nomenclature so Watson & Crick used a common name.

The first sentence is a classic understatement and you can be sure that it's written by Crick and not Watson.

A structure for nucleic acid has already been proposed by Pauling and Corey¹. They kindly made their manuscript available to us in advance of publication. Their model consists of three intertwined chains, with the phosphates near the fibre axis, and the bases on the outside. In our opinion, this structure is unsatisfactory for two reasons:

(1) We believe that the material which gives the X-ray diagrams is the salt, not the free acid. Without the acidic hydrogen atoms it is not clear what forces would hold the structure together, especially as the negatively charged phosphates near the axis will repel each other.

(2) Some of the van der Waals distances appear to be too small.

At the time they wrote the paper, Pauling had not seen their model so Watson & Crick were not certain that he would agree with them. (See Linus Pauling's notes taken during the meeting with Watson & Crick on April 8, 1953.) They were obliged to insert some commentary about competing ideas concerning the structure of DNA, especially the Pauling & Cory model that had just been published several weeks earlier in the Proceedings of the National Academy of Sciences (USA) [Pauling & Cory, 1953]. (The three-stranded structure of DNA from the Pauling & Cory paper is shown above.)

No doubt Watson & Crick were delighted to be able to correct the famous Linus Pauling. The idea that Pauling might have got the structure wrong because of simple mistakes like packing charged molecules together and not allowing for proper van der Waals distances was too tempting to omit.

Another three-chain structure has also been suggested by Fraser (in the press). In his model the phosphates are on the outside and the bases on the inside, linked together by hydrogen bonds. This structure as described is rather ill-defined, and for this reason we shall not comment on it.

Bruce Fraser published a brief note where he took issue with the Pauling & Cory paper but, as Watson and Crick note, the proposed structure is not described in any detail. There are no figures. The Fraser manuscript is here].

We wish to put forward a radically different structure for the salt of deoxyribose nucleic acid. This structure has two helical chains each coiled round the same axis (see diagram). We have made the usual chemical assumptions, namely, that each chain consists of phosphate diester groups joining beta-D-deoxyribofuranose residues with 3',5' linkages. The two chains (but not their bases) are related by a dyad perpendicular to the fibre axis. Both chains follow right-handed helices, but owing to the dyad the sequences of the atoms in the two chains run in opposite directions. Each chain loosely resembles Furberg's² model No. 1; that is, the bases are on the inside of the helix and the phosphates on the outside. The configuration of the sugar and the atoms near it is close to Furberg's "standard configuration," the sugar being roughly perpendicular to the attached base. There is a residue on each every 3.4 A. in the z-direction. We have assumed an angle of 36° between adjacent residues in the same chain, so that the structure repeats after 10 residues on each chain, that is, after 34 A. The distance of a phosphorus atom from the fibre axis is 10 A. As the phosphates are on the outside, cations have easy access to them.

Everything important about the structure of DNA is contained in this paragraph except for the base pairs. Note how important it was to confirm that the nucleotide conformation is similar to that which Furberg saw in the structure of cytidylate.

The important points about the backbone chains are that there are only two of them, that they form a regular helix, and the chains run in opposite directions. Recall that it was Crick who recognized the the chains had to be anti-parallel and nobody else, including Franklin and Wilkins, had thought of this.

The structure is an open one, and its water content is rather high. At lower water contents we would expect the bases to tilt so that the structure could become more compact.

This is an oblique reference to the A form of DNA that Rosalind Franklin was working on. The A form is somewhat dehydrated and the helix is more compact. Just as Watson & Crick predict, the bases are tilted in the A form.

The novel feature of the structure is the manner in which the two chains are held together by the purine and pyrimidine bases. The planes of the bases are perpendicular to the fibre axis. They are joined together in pairs, a single base from one chain being hydroden-bonded to a single base from the other chain, so that the two lie side by side with identical z-coordinates. One of the pair must be a purine and the other a pyrimidine for bonding to occur. The hydrogen bonds are made as follows: purine position 1 to pyrimidine position 1; purine position 6 to pyrimidine position.

If it is assumed that the bases only occur in the structure in the most plausible tautomeric forms (that is, with the keto rather than the enol configurations) it is found that only specific pairs of bases can bond together. These pairs are: adenine (purine) with thymine (pyrimidine), and guanine (purine) with cytosine (pyrimidine).

The pairing of A with T and G with C to form base pairs in the middle of the helix is the most important part of the proposed structure. It could not have been determined from the X-ray diffraction data. It could only be deduced by model building. Note that Watson & Crick emphasize the correct tautomeric forms of the bases since most of the textbooks of the day showed the incorrect forms.

In other words, if an adenine forms one member of a pair, on either chain, then on these assumptions the other member must be thymine; similarly for guanine and cytosine. The sequence of bases on a single chain does not appear to be restricted in any way. However, if only specific pairs of bases can be formed, it follows that if the sequence of bases on one chain is given, then the sequence on the other chain is automatically determined.

This is the idea of complementarity that was very much in the air among the insiders. It's an entirely theoretical idea but the fact that the structure conformed made it all that much more elegant a solution. The "beauty" of the structure derives in large part from the fact that it explains so much.

It has been found experimentally^3,4 that the ratio of the amounts of adenine to thymine, and the ratio of guanine to cytosine, are always very close to unity for deoxyribose nucleic acid.

This is a reference to the Chargaff ratios.

It is probably impossible to build this structure with a ribose sugar in place of the deoxyribose, as the extra oxygen atom would make too close a van der Waals contact.

An insight that proved to be correct. The Watson & Crick structure explains one more thing that none of the other structures could explain.

The previously published X-ray data^5,6 on deoxyribose nucleic acid are insufficient for a rigorous test of our structure. So far as we can tell, it is roughly compatible with the experimental data, but it must be regarded as unproved until it has been checked against more exact results. Some of these are given in the following communications. We were not aware of the details of the results presented there when we devised our structure, which rests mainly though not entirely on published experimental data and stereochemical arguments.

Watson & Crick know full well that their structure is compatible with published data from Astbury (ref. 5) and Wilkins & Randall (ref. 6). They also know that some of the key features of their model, such as base pairing, cannot be verified by X-ray crystallographic data from DNA fibers fibres.

They make reference to the accompanying papers by Franklin & Gosling and by Wilkins, Stokes, and Wilson ("following communications"). This was a standard way of referring to papers that were in press but Watson & Crick have been criticized for not mentioning the authors by name, especially Rosalind Franklin and Maurice Wilkins.

The last sentence has been widely interpreted as somewhat disingenuous. Of course they were aware of the results, including many of the details that had not been published (see below). A great deal of the structure of the backbones was informed by the results from Franklin's unpublished X-ray images of B-DNA. It would have been much better if Watson & Crick had stated here—as a personal communication—that they had received information from Wilkins and Franklin.

It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.

Another very famous sentence from the paper and another classic example of understatement. Watson & Crick follow up on this with another Nature paper that describes how DNA replication should work. The fact that an obvious mechanism of replicating DNA is apparent from looking at the structure is another example of its beauty and elegance. These were the sorts of thing that made the structure so appealing to those who were working on these problems. On the other hand, they meant nothing to most biologists, many of whom were not inclined to believe the Watson & Crick structure when it was first published. Remember that for most biologists this was the first time they were confronted with the idea that DNA was important. Watson & Crick had know for years that DNA was the secret of life but the rest of the world still thought DNA was unimportant.

Full details of the structure, including the conditions assumed in building it, together with a set of coordinates for the atoms, will be published elsewhere

The "details" were published in The Proceeding of the Royal Society in January, 1954.

We are much indebted to Dr. Jerry Donohue for constant advice and criticism, especially on interatomic distances. We have also been stimulated by a knowledge of the general nature of the unpublished experimental results and ideas of Dr. M. H. F. Wilkins, Dr. R. E. Franklin and their co-workers at King’s College, London. One of us (J. D. W.) has been aided by a fellowship from the National Foundation for Infantile Paralysis.

One of the myths that has grown up about the discovery of the double helix is that Watson & Crick never acknowledged Franklin and Wilkins. This myth is due, in part, to the fact that Wilkins and Franklin are not mentioned in the body of the paper where it would have been appropriate (see above). However, they are clearly mentioned in the acknowledgments even though the reference seems to contradict their earlier statement about being unaware of unpublished results.