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Wednesday, March 19, 2008

Nobel Laureate: Paul Flory

 

The Nobel Prize in Chemistry 1974.

"for his fundamental achievements, both theoretical and experimental, in the physical chemistry of the macromolecules"


In 1974, Paul J. Flory (1910 - 1985) was awarded the Nobel Prize in Chemistry for his work on the physical chemistry of macromolecules in solution. His work led to an understanding of the dynamics and conformation of proteins and that's why his contributions are covered in biochemistry courses.

The presentation speech was delivered by Professor Stig Claesson of the Royal Academy of Sciences.THEME:

Nobel Laureates
Your Majesty, Your Royal Highnesses, Ladies and Gentlemen,

This year's Nobel prize in chemistry has been awarded to Professor Paul Flory for his fundamental contributions to the physical chemistry of macromolecules.

Macromolecules include biologically important materials such as cellulose, albumins and nucleic acids, and all of our plastics and synthetic fibers.

Macromolecules are often referred to as chain molecules and can be compared to a pearl necklace. They consist of long chains of atoms which, when magnified one hundred million times, appear as a pearl necklace. The pearls represent the atoms in the chain. One should realize that this chain is much longer than the necklaces being worn here this evening. To obtain a representative model of a macromolecule all of the necklaces here in this hall should be connected together in a single long chain.

One can readily appreciate that the development of a theory for these molecules presented considerable difficulties. The forms of the chain itself, whether extended or coiled, represents a property difficult to rationalize.

A statistical description is of necessity required, and Professor Flory has made major contributions to the development of such a theory. The problem is more difficult, however. How can one compare different molecules in different solvents?

When chain molecules are dissolved in different solvents they become coiled to different degrees, depending on the interaction between repulsive and attractive forces in the solution. In a good solvent the chain molecules are extended. In a poor solvent, in contrast, the chain molecules assume a highly coiled form.

Professor Flory showed that if one takes a solution of extended chain molecules in a good solvent, and slowly cools the solution, then the molecules become progressively more coiled until they are no longer soluble.

Thus, there must be an intermediate temperature where the attractive and repulsive forces are balanced. At this temperature the molecules assume a kind of standard condition that can be used, generally, to characterize their properties.

This temperature Professor Flory named the theta temperature. A corresponding temperature exists for real gases at which they follow the ideal gas law. This temperature is called the Boyle temperature after Robert Boyle who discovered the gas laws. By analogy, the theta temperature for macromolecules is often referred to as the Flory temperature.

Profssor Flory showed also that it was possible to define a constant for chain molecules, now called Flory's universal constant, which can be compared in significance to the gas constant.

When one, in retrospect, reads about an important scientific discovery, one often feels that the work was remarkably simple. This actually indicates, however, that it was brilliant insight in a new and until then unexplored research area. This is highly characteristic of Professor Flory's scientific discoveries, not only those concerned with the Flory temperature and Flory's universal constant but also many of his other important research studies. Further examples are found in his investigation of the relationship between the reaction mechanism and the length of the chains formed when chain molecules are prepared synthetically, as well as his important contribution to the theory of crystallization and rubber elasticity. These achievements have been of major importance for technological developments in the plastics industry.

In recent years Professor Flory has investigated, both theoretically and experimentally, the relation between rotational characteristics of the chain links and the form of the chain molecules. This is of fundamental significance for the understanding of both biological macromolecules and synthetic chain molecules.

During the time Professor Flory has been active as a scientist, macromolecular chemistry has been transformed from primitive semi-empirical observations into a highly developed science. This evolution has come about through major contributions by research groups from both universities and many of the world's largest industrial laboratories. Professor Flory has remained a leading researcher in the area during this entire period, giving further evidence of his unique position as a scientist.

Professor Flory,

I have tried to describe briefly the fundamental importance of your many contributions to macromolecular chemistry and in particular those concepts introduced by you and now referred to as the Flory-temperature and the Flory universal constant.

On behalf of the Royal Academy of Sciences I wish to convey to you our warmest congratulations and I now ask you to receive your prize from the hands of His Majesty the King.


Gene Genie #27

 
The 27th edition of Gene Genie has been posted at DNA Direct Talk [The Gene Genie: Yes, But What About Me?].
Welcome to another edition of Gene Genie, the blog carnival about genes, genomics and gene-related diseases. With Craig Venter and 23andMe and decodeME all over the news, I thought this edition might be appropriately focused on genes and “me.” What does the gene genie have to say about us?
The beautiful logo was created by Ricardo at My Biotech Life.

The purpose of this carnival is to highlight the genetics of one particular species, Homo sapiens.


Dawn of Man

 
In his tribute to Arthur C. Clarke, John Dennehy mentions the opening scene from 2001: A Space Odyssey [Goodbye Arthur C. Clarke]. That was a scene that made a big impression on me as well, although I was a good deal older than John when I first saw it. Here it is.




Arthur C. Clarke (1917 - 2008)

 

Science can destroy religion by ignoring it as well as by disproving its tenets. No one ever demonstrated, so far as I am aware, the non-existence of Zeus or Thor - but they have few followers now.

                                                      Arthur C. Clarke

It may be that our role on this planet is not to worship God-but to create him.

                                                      Arthur C. Clarke

I don't believe in God but I'm very interested in her.

                                                      Arthur C. Clarke

The greatest tragedy in mankind's entire history may be the hijacking of morality by religion.

                                                      Arthur C. Clarke

Information is not knowledge1, knowledge is not wisdom, and wisdom is not foresight. Each grows out of the other, and we need them all.

                                                      Arthur C. Clarke


1. This simple statement of fact is much more important in today's world than most people realize. Information should not be confused with knowledge.

[Photo Credit: ABCNews - Arthur C Clarke turns 90]

Billboard Censorship

 
According to the Grand Rapids Press, the Freedom From Religion Foundation is having trouble renting billboard space to advertise its message "Beware of Dogma" [Atheists claim censorship by billboard company].
The group that asked Hudsonville to remove God from the city's mission statement says it is having a hard time placing a billboard espousing its position.

"This is new, that a billboard company is censoring us," said Annie Laurie Gaylor, co-president of the Freedom From Religion Foundation. The Madison, Wis.-based group, dedicated to the separation of church and state, bills itself as North America's largest group of atheists and agnostics with 12,000 supporters.

The billboard with the words "Beware of Dogma" and the group's Web address has been used around the country, she said.

Gaylor said CBS Outdoor Advertising in Grand Rapids declined to rent a billboard to Freeedom From Religion, telling her it had been through controversy in the past and community reaction would force the billboard down within a day. She is working with other area firms, she said, but their locations are not her first choice.
We discussed this issue before when I declared that this was a "freedom of speech" issue [What Freedom of Speech Really Means]. Many readers disagreed , stating that a private company had the right to discriminate on the basis of religious beliefs (or lack of them).

This time there's a very interesting discussion going on at RichardDawkins.net [ Atheists claim censorship by billboard company]. Read the comments on that site.

This is clearly a gray area but, personally, I'd like to live in a society where a private billboard company wasn't afraid to rent space to all kinds of groups—including those groups whose opinions aren't shared by the management of the company. I'd like to live in a society where everyone understood that this was ethical behavior on the part of the billboard company and they didn't hold the company responsible for the message on the billboard. Even better would be to live in a society where the average person celebrated diversity of opinion and looked forward to seeing and hearing about contrary views. They would also look forward to debating and discussing those views.1


1. In case anyone is wondering whether this can be construed as support for teaching the controversy, the answer is yes. I think Christian private schools should be teaching about evolution and the scientific views on the age of the Earth. I think public school students should be discussing the conflict between evolution and creationism (and science vs. religion).

[Photo Credit: More Billboards in Chambersburg PA]

Tuesday, March 18, 2008

Are You as Smart as a Third Year University Student? Q7

 
Question 1
Question 2
Question 3
Question 4
Question 5
Question 6
Choose the INCORRECT statement about protein folding.

a) protein folding is a cooperative phenomenon
b) the energy of the final folded protein is at the bottom of a free energy well
c) most proteins fold extremely rapidly
d) folding is an enthalpy-driven reaction (ΔH)
e) protein folding can be assisted by molecular chaperones


Are You as Smart as a Third Year University Student? Q6

 
Question 1
Question 2
Question 3
Question 4
Question 5
Here are the names and structures of the aldohexoses. The common ones in biology are shown in blue.


Identify the monosaccharide shown below in three different views.



               a) D-allose
               b) D-altrose
               c) D-galactose
               d) D-glucose
               e) D-mannose


THEME: Protein Structure

 
Jan. 28, 2007
Free Love, the '60's, and Protein Synthesis

Feb. 8, 2007
How Proteins Fold

Feb, 11, 2007
Heat Shock and Molecular Chaperones

Feb. 13, 2007
Disulfide Bridges Stabilize Folded Proteins

THEME:

More posts on
Protein Structure
Feb. 14, 2007
The Anfinsen Experiment in Protein Folding

Feb. 15, 2007
Gene HSPA5 Encodes BiP-a Molecular Chaperone

Feb. 20, 2007
Glycoproteins

Feb. 27, 2007
Collagen

March 12, 2007
How Cells Make Tryptophan, Phenyalanine, and Tyrosine

June 5, 2007
Protein Turnover

July 10, 2007
Fixing Carbon: the Structure of Rubisco

Aug. 1, 2007
Hemoglobin

Aug. 1, 2007
Myoglobin

Aug. 1, 2007
Heme Groups


Oct.13, 2007
HSP90 Structure

March 2, 2008
The α Helix

March 10, 2008
β Strands and β Sheets

March 13, 2008
Loops and Turns

March 13, 2008
Levels of Protein Structure

March 13, 2008
Examples of Protein Structure

March 14, 2008
Evolution and Variation in Folded Proteins


April 3, 2008
The Peptide Bond

April 3, 2008
Ramachandran Plots

April 4, 2008
Levinthal's Paradox

April 6, 2008
One Protein - Two Folds


Monday, March 17, 2008

A Challenge to Jonathan Wells

 
On February 29th Jonathan Wells published a short review of a scientific paper by Maurice et al. (2008). You can read the original Wells posting at: The Irrelevance of Darwinian Evolution to Antibiotic Resistance.

Wells was trying to make a point. Concerning the work from Dardel's lab (Maurice et al, 2008), Wells claimed ...
Yet Darwinian evolution had nothing to do with it.

First, some bacteria happen to have a very complex enzyme (acetyltransferase), the origin of which Darwinism hasn’t really explained. Come to think of it, most cases of antibiotic resistance (including resistance to penicillin) involve complex enzymes, and the only “explanations” for them put forward by Darwinists are untestable just-so stories about imaginary mutations over unimaginable time scales.

Second, the acetyltransferase story is about minor changes in an existing species of bacteria. But Darwin’s theory isn’t really about how existing species change over time. People had been observing those long before 1859, and most of the new insights we’ve gained since then have come from genetics, not Darwinism. Yet Mendel’s theory of genetics contradicted Darwin’s, and Darwinists rejected Mendelian genetics for half a century. And although an understanding of genetics is important when dealing with antibiotic resistance, Darwin’s theory of the origin of species by natural selection is not.

Third, Dardel and his colleagues made their discovery using protein crystallography. They were not guided by Darwinian evolutionary theory; in fact, they had no need of that hypothesis.
We all know how creationists use the word "Darwinism." Most of the time, it's a synonym for evolution. All of the time, it's an attempt to obfuscate and confuse their audience. What Wells is saying is that evolution had nothing to do with the paper. All that happened was a bit of genetics. According to Wells, "Darwin's theory of the origin of species by natural selection" was not involved.

The senior author of the paper posted a comment on Pharyngula saying, "Actually, we did indeed use darwinian evolution within this work (something unusual in structural biology)." [see Why the Right People Hate IDiots, and links within that posting].

Michael Egnor gallops to the defense of his hero. Today he posted a rebuttal to my criticism of him and Wells [Dr. Larry Moran, Darwinism, and Vicious Personal Invective]. Here's what Egnor says,
Dr. Wells pointed out that research on antibiotic resistance wasn’t guided by Darwinian evolutionary theory. That evolution occurred — that is, that the population of bacteria changed over time — is obviously true, and obviously was relevant to the antibiotic resistance research. Dr. Wells made the observation that the research owed little to Darwin’s theory that all biological complexity arose by natural selection without teleology.
This is an incredible admission from a creationist. Egnor admits that the bacteria evolved. He then goes on to define some bizarre version of "Darwin's theory."1 But the cat is out of the bag. What we see here folks, is the recognition that there is a distinction between Darwinism and evolution by natural selection. We're still not clear about the difference but it seems that bacteria can evolve resistance to antibiotics.

Egnor admits that the paper used evolution but it just wasn't Darwinism.

Now let's see if Jonathan Wells agrees. I'll apologize to Wells if he will post a comment here, or on Evolution News & Views, agreeing to the following ..
I, Jonathan Wells, agree that Maurice et al. (2006) employed evolution by natural selection in their methodology. My position is that evolution by natural selection is not what I mean when I use the word Darwinian.
Note that I'm not asking him to agree that "Darwinism" was involved in the paper. All he has to do is admit that evolution by natural selection is not what he means when he uses the word "Darwinian."

Michael Egnor has indicated that this is what Wells actually means. Now let's see if Wells himself will admit it.


1. The standard version of Darwin's Theory of Evolution by Natural Selection is that populations evolve due to the differential survival of individuals with a fitter genotype.

Maurice, F., Broutin, I., Podglajen, I., Benas, P., Collatz, E. and Dardel, F. (2008) Enzyme structural plasticity and the emergence of broad-spectrum antibiotic resistance. EMBO Rep. 2008 Feb 22 [Epub ahead of print] [PubMed]

What Is Consciousness?

 
There are two broad traditional and competing metaphysical views concerning the nature of the mind and conscious mental states: dualism and materialism. While there are many versions of each, the former generally holds that the conscious mind or a conscious mental state is non-physical in some sense. On the other hand, materialists hold that the mind is the brain, or, more accurately, that conscious mental activity is identical with neural activity.

Consciousness
There were lots of interesting things going on at SciBarCamp over the weekend but I want to pick out one topic that came up several times.

At one point there was a group of us talking about a number of different things when the topic of consciousness arose. One member of the group happened to mention that humans were special because they are "conscious."

Now, I happen believe that there's no such thing as "consciousness" in the sense of something tangible that we can point to and say. "That's consciousness." I think it's merely a descriptive term for brain activity. It's an epiphenomenon. Consciousness may be an important and useful word for describing the phenomenon but that's all it is. I don't know whether an octopus is conscious, or a dolphin, or a dog, or a chimpanzee. The reason I don't know this is because nobody can tell me what consciousness is.

Nobody in the group seemed to share my view. They all seemed to think that consciousness was something tangible and real—something that set humans off from the rest of life. Lee Smolin, a physicist at the Perimeter Institute, was particularly vocal about this. He expressed a great deal of surprise at the fact that anyone could question the existence of consciousness. In fact, Smolin insisted that the onus was on me to prove that consciousness doesn't exist.

I tried out some of my standard approaches on the group. For example, I asked them whether the character Data on Star Trek (TNG) was conscious. (The question applies equally well to any sophisticated robot.) Several people said yes. To me, this means that they define consciousness as simply complex electronic activity. If a robot/android can possess consciousness then how, exactly, do you define consciousness as anything else?

Other weren't sure whether Data was conscious or not. Unfortunately, they weren't able to explain why Data was not conscious and the other members of the Star Trek crew were conscious. At that point the group broke up because sessions were starting. My suspicion is that some people at the meeting were true dualists and they had never thought seriously about any other possibility.

The question is complex. Even a cursory review of the Wikipedia entry will be enough to confuse almost everyone [Consciousness]. What surprised me the most about the group I was talking to is that they seemed to take for granted that there was such a thing as a meaningful definition of consciousness that could be used to separate humans from all other animals. Some of them seemed to be genuinely puzzled by the fact that they couldn't define consciousness. It was as though they had never thought about the problem before.

The question came up again in the afternoon when I attended a discussion led by Robert Sawyer. Sawyer is a science fiction author, and a very good one at that. One of his books Calculating God is an excellent story about discovering God. I highly recommend it. His latest book is Rollback and I will be buying a copy as soon as I get to a bookstore.

I've met Robert Sawyer before. He's been to Skeptics meetings and to the Centre for Inquiry. He's a smart guy, and he knows it. I like people like that.

Sawyer is currently working on a series of books where the World Wide Web acquires consciousness. He organized a session to talk about his books under the title "World Wide Web Gaining Consciousness." As he explained it, this was supposed to be a brainstorming session to help him with his book. It was also pretty good publicity.

Sawyer began by explaining that consciousness evolved in humans about 40,000 years ago. We know this, according to Sawyer, because that's when we see the first signs of human adornment. Apparently, the ability to be self-aware is the hallmark of consciousness. In his book, the World Wide Web becomes self-aware and conscious.

There was a lot of discussion about what it meant for the WWW to be conscious. There were some questions about how the characters in the book knew that the WWW had become conscious. This was quite interesting. Most of the people in the room seemed to be having some difficulty understanding what it meant for Web to be conscious.

At one point I asked whether consciousness was ever defined and whether the characters in the book discussed the idea that there might not be any such thing as consciousness. Sawyer responded that, of course, everyone thinks about such things and so will his characters. I mentioned that some people don't seem to know about the difficulty in defining consciousness and don't seem to have thought about the fact that it may not actually exist.

I called for everyone to raise their hands if they had thought about the idea that consciousness may not exist. Everyone raised their hands. This is when Sawyer said that it's not a good idea to think you are the smartest person in the room, Larry.

It was embarrassing. The result of the survey indicated that everyone in the room had pondered the consciousness problem and all but one (me) had reached the same conclusion after careful thought. Consciousness, which none of them could define, exists and furthermore, it evolved uniquely in humans in the recent past.1 Whatever it is, the same kind of consciousness was also able to arise spontaneously in a network of fiber optic cables.

I admit I was wrong. The evidence is clear. All smart people have thought about these things. Most of them have made a "conscious" decision to be dualists and reject the notion of consciousness as a mere epiphenonenon. The lunch group seems to have been an exception.

Later on the the same session, another science fiction writer named Peter Watts mentioned that consciousness arose by natural selection. I pointed out that there was another possibility; namely that it could evolve by accident. This would be similar to how it evolved in the World Wide Web. (Sawyer did not indicate that natural selection was involved there.) Peter assured me in no uncertain terms that he knew as much about evolution as I did.

Science fiction writers sure know a lot of things.

In case you want the see another version of this story go to Robert Sawyer's blog and read what he has to say about this discussion [SciBarCamp].


1. I wonder how this actually worked. Since consciousness evolved it must have a genetic component. Otherwise it's not evolution. Presumably a mutation causing consciousness arose some 40,000 years ago. It rapidly spread though the population in a short period of time. It must have been interesting times. In some families you would have had a mixture of children; some were conscious and some were not. How did they tell which was which?

Happy St. Patricks Day!!!

 

Today's the day when the Irish—and people who want to be Irish—celebrate by doing typically Irish things; like drinking green beer, dancing Irish jigs, and going to mass. (?)1

My ancestors on my mother's side are (mostly) Irish. My grandfather was a Doherty (O'Doherty). That's the name at the top of the map in country Donegal. That side of the family came to Canada in 1802 and the Irish blood has been diluted—most notably by American refugees from the Revolutionary War (United Empire Loyalists) (gasp!).

The O'Doherty's are descended from Niall Noigíallach who kidnapped St. Patrick.

My grandmother was a Foster from Fermanagh. That's by the two lakes (Lower Lough Erne and Upper Lough Erne) in the upper central part of the country near the seat of the Maguires. Her family came to Canada in 1865 but both of her parents were Irish so at least 1/4 of my genes are undiluted Irish. I'll drink to that.

We don't talk about the nasty little fact that the Foster's were probably English invaders from the 1600's. As they say, somebody had to civilize the Irish and it might as well have been the English!

One of the reasons why the topic was avoided by my grandparents was because the O'Doherty clan was almost wiped out by the English during the O'Doherty rebellion in 1608 led by Sir Cahir O’Doherty. Some of the survivors had to flee to Skye to avoid being hung. I descend from those refugees.




1. This entire post is a copy of my first St. Patrick's Day post in 2007.

Monday's Molecule #65

 
Some of the most important contributions to the biological sciences aren't associated with a particular molecule. This is one of those cases.

The figure on the right is taken from the Nobel Lecture of the Laureate who will be featured on Wednesday. It illustrates the problem that was being addressed. The real contribution of this Nobel Laureate is more easily illustrated by using a mathematical equation. The equation is shown below.

Your task is to identify the general field that's being discussed and to describe the significance of the equation. You must explain all the variables in the equation and why it was important enough to contribute to the award of a Novel Prize. Naturally, you also have to name the Nobel Laureate.

The first person to correctly describe the equation and name the Nobel Laureate wins a free lunch at the Faculty Club. Previous winners are ineligible for one month from the time they first collected the prize. There is only one ineligible candidate for this week's reward.

THEME:

Nobel Laureates
Send your guess to Sandwalk (sandwalk (at) bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the equation and the Nobel Laureate(s). Note that I'm not going to repeat Nobel Laureates so you might want to check the list of previous Sandwalk postings.

Correct responses will be posted tomorrow along with the time that the message was received on my server. I may select multiple winners if several people get it right.

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

UPDATE: We have a winner! Haruhiko Ishii of the Dept. of Physics at UCSD got the right answer. I've issued an invitation to meet for lunch.

The figure shows the transition from a random coiled polymer to one that has more structure. The process was studied by Paul Flory who won the Nobel Prize in 1974 for his work on the physical chemistry of macromolecules. One of his important contributions was the concept of intrinsic viscosity [η]. This is a measure of viscosity that takes into account the contribution of a solute. The intrinsic viscosity depends on the viscosity of the solvent in the absence of solute and the change that takes place when the solute occupies a certain volume of the solution.

The equation for solving intrinsic viscosity can be written several ways. In the example shown above, K and α represent constants that depend on the type of solute. M is the molecular weight of the polymer.


IDiots Get Public Funding for their Schools in Alberta

 
Scott Rowed is one of the Alberta representatives for the Centre for Inquiry. He has an op-ed piece in Saturday's Edmonton Journal where he points out the dangers of giving public money to faith-based schools. These schools are permitted by law to discriminate on the basis of religious belief. That's not new. Here in Ontario we have a Roman Catholic school system that is fully funded by taxpayer money.

The shocking thing is the extent to which some faith-based schools will go to exclude rational thought and genuine education. For example, Scott says,
To have this choice of placing their children into a faith school, parents must obtain a letter from a preacher praising their church devotion and sign a statement of faith. This quote, from the constitution and bylaws of Fort McMurray Christian School Society, is typical: "We believe the Genesis account of creation is to be understood literally; that man was created in God's own image and after His own likeness; that man's creation was not by evolution or change of species or development through interminable periods of time from lower to higher form."

Parents who believe that the first cowboy saddled up a triceratops have more choice as their children can attend either a faith school or a public school. On the other hand, Christians who accept evolution, non-believers, and followers of other faiths can enrol their children only in a public school.
I agree with Scott. This is outrageous. Any school system that explicitly denies one of the fundamental facts of science should not receive a single penny of taxpayer's money.1

There's only one rational solution to the problem. The government must fund a single secular school system. That means eliminating funding for the Catholic schools as well as the IDiot schools. If you live in Ontario, join the One School System Network and work toward achieving this goal.


1. I wonder if Ben Stein will make a movie about this kind of discrimination? It's obvious that any teacher who believes in evolution will never get a job in one of these schools and any student who starts to believe in evolution will be EXPELLED.

[Photo Credit: Rahime at Prayer for Rain]

Friday, March 14, 2008

A Visit to Guelph

 
Next Wednesday I'll be visiting Guelph University (Ontario, Canada) to give a lecture on "Evolution as a Fact and a Theory." The hosts are Guelph Skeptics [Lecture].

Maybe I'll see some of you there?


Evolution and Variation in Folded Proteins

As a general rule, the primary structure of a protein (amino acid sequence) ultimately determines it's final three-dimensional shape1. Proteins fold spontaneously to adopt a specific structure that minimizes free energy. The folded protein occupies the bottom of a free energy well [How Proteins Fold, The Anfinsen Experiment in Protein Folding, Disulfide Bridges Stabilize Folded Proteins, Heat Shock and Molecular Chaperones].

Each protein has a characteristic shape associated with its function. When we discuss the evolution of proteins, we like to divide the residues into three categories as shown below for the structure of myoglobin from sperm whale (Physeter catodon) [PDB 1A6M].

Myoglobin is a small protein with a bound heme group (shown as a space-filling molecule). It carries oxygen in the bloodstream and tissues. The oxygen molecule binds to the active site of the protein near one side of the heme group. There are specific amino acid residues at the active site that are absolutely required for binding oxygen. As you might expect, these amino acids are highly conserved—they will be found at that position in myoglobin from humans or any other species.

The second category of amino acid residues makes up the hydrophobic interior of the protein. Myoglobin is an all-α-helical protein and several of the helices group together to form a helix bundle. The interior of that bundle consists largely of hydrophobic amino acid residues. This is what stabilizes the three-dimensional structure and causes the polypeptide chain to spontaneously fold after it is synthesized.

The third category of residues is the surface residues. These are usually hydrophilic residues that interact with the surrounding water. The surface residues don't make as much of a contribution to the overall three-dimensional structure so their exact composition can be quite variable.

The class of proteins to which myoglobin belongs is called "globins." There are two other globins that you are probably familiar with: α-globin and β-globin are the two polypeptides that come together to form an α2β2 hemoglobin tetramer.

The three proteins (myoglobin, α-globin, and β-globin) descended by gene duplication from a common ancestral globin several hundred million years ago. Today their amino acid sequences are quite different due to the accumulation of random mutations and fixation by random genetic drift. In spite of the differences in primary structure, the three-dimensional structures of the three proteins are very similar. This can easily be shown by superimposing the three structures as shown in the figure (myoglobin=green, α-globin=blue, β-globin=purple).

Most people don't appreciate the amount of variation that underlies this conserved three-dimensional structure. It's worth taking a look at a bunch of aligned globin sequences from different species to see exactly which amino acids are highly conserved and which positions can tolerate almost any amino acid.

Let's go to the Pfam (protein family) database at the Sanger Institute in Cambridge (UK). The entry for the globin family is Globin PF00041. Click on "Alignments" in the left sidebar. This link takes you to the alignment page where you can create an alignment of all the known globin sequences. Choose 75 seeds (default) in the first table and select "Pfam viewer" from the pull-down menu under "Viewer." Click "View" to see the alignments.

Highly conserved amino acid residues are highlighted by vertical shading in the Pfam view. The first thing you should notice is that there are very few amino acids that are invariant. The conserved residue on the left (blue) is tryptophan (W). It's present in most of the globins from different species but not all. Look at the other positions and note that in most cases a variety of different amino acid residues can be substituted. Sometimes only hydrophobic residues (blue) can be found at a particular site and sometimes there are other restricted choices. Lots of insertions and deletions (dots) can be tolerated without major disruption to the overall three-dimensional structure.

Data like this reveals that the amino acid residues in the active site are usually conserved. Residues in the hydrophobic core are moderately conserved. And residues on the surface are hardly conserved at all.

The point is that there are literally billions of different proteins that have the same shape as globins and still function as carriers of oxygen. This is an important point. Opponents of evolution often take a single globin from a single species and calculate the probability that such a structure will form. They assume that only one out of twenty amino acids can be found at each position and the resulting probability (e.g., 20020) is enormous. Thus, they conclude, such a protein could never form by chance. They don't seem to appreciate the fact that we already know of billions of different proteins that can function as globins.

There are many other examples of this observation. The four structures below show the conformation of the cytochrome c polypeptide chain from tuna, rice, yeast, and a bacterium. The amino acid sequences have diverged considerably from their common ancestor of 3 billion years ago but the structures are very similar.

We conclude that the amino acid sequence of a polypeptide determines how it will fold in three-dimensional space but there are billions of different amino acid sequences that will adopt the same structure.

Finally, let's look at a more complicated example. The enzymes lactate dehydrogenase (below left) and malate dehydrogenase (below right) share a common ancestor even though they are different enzymes. This is a case where substitutions of amino acid residues in the active site gave rise to a new activity. Today the amino acid sequence similarity is barely above the threshold for defining homology but the structures are still very similar.




1. Other factors that contribute are bound ligands, such as heme groups, and interactions with other proteins as in multimeric proteins with sifferent subunits.

Escalators Are Dangerous

 
From Science News [Rate Of Escalator Injuries To Older Adults Has Doubled]
Using U.S. Consumer Product Safety Commission data, the researchers found nearly 40,000 older adults were injured on escalators between 1991 and 2005. The most frequent cause of injury was a slip, trip or fall resulting in a bruise or contusion. The most common injuries were to the lower extremities. However, most injuries were not serious. Only 8 percent of the 39,800 injured were admitted to the hospital after evaluation in an emergency department.

"Although escalators are a safe form of transportation, fall-related injuries do occur. Older adults, especially those with mobility, balance or vision problems, should use caution while riding an escalator and especially when stepping on or off. They should not try to walk up or down a moving escalator, carry large objects, or wear loose shoes or clothing while riding since these appear to be associated with an increased risk of falling," said Dr. O'Neil, associate professor of clinical pediatrics at the IU School of Medicine.




500,000 Visitors

 
Sometime on Wednesday night Sandwalk notched up 500,000 visitors. To put this in perspective, after 16 months of blogging the total number of visitors is less than half the number who visit Pharyngula in one month.

This is depressing. We need to do something about it. Is there any way we can shut down Pharyngula?




Fractal Wrongness

 

From Kuenwoo Lee (may not be original) ...
Fractal Wrongness

The state of being wrong at every conceivable scale of resolution. That is, from a distance, a fractally wrong person's worldview is incorrect; and furthermore, if you zoom in on any small part of that person's worldview, that part is just as wrong as the whole worldview.

Debating with a person who is fractally wrong leads to infinite regress, as every refutation you make of that person's opinions will lead to a rejoinder, full of half-truths, leaps of logic, and outright lies, that requires just as much refutation to debunk as the first one. It is as impossible to convince a fractally wrong person of anything as it is to walk around the edge of the Mandelbrot set in finite time.

If you ever get embroiled in a discussion with a fractally wrong person on the Internet--in mailing lists, newsgroups, or website forums--your best bet is to say your piece once and ignore any replies, thus saving yourself time.


The image is "borrowed" from Jeffrey Shallit's blog Recursivity [Fractal Wrongness]

Thursday, March 13, 2008

Examples of Protein Structure

Here's a slideshow of figures from Horton et al. (2006) showing cartoons of various proteins. At first it seems as though every protein is completely different but after a while you begin to notice that there are recurring motifs—especially β sheets in the hydrophobic core of a domain.



Click here to see a full-screen version of the slideshow. More adventuresome readers might want to visit the actual structures on the Protein Data Base (PDB). Here are the links to each PDB record. References to the people who solved the structure can be found in the PDB record.
  • Human (Homo sapiens) serum albumin [PDB 1BJ5] (class: all-α). This protein has several domains consisting of layered α helices and helix bundles.
  • Escherichia coli cytochrome b562 [PDB 1QPU] (class: all-α). This is a heme-binding protein consisting of a single four-helix bundle domain.
  • Escherichia coli UDP N-acetylglucosamine acyl transferase [PDB 1LXA] (class: all-β). The structure of this enzyme shows a classic example of a β-helix domain.
  • Jack bean (Canavalia ensiformis) concanavalin A [PDB 1CON] (class: all-β). This carbohydrate-binding protein (lectin) is a single-domain protein made up of a large β-sandwich fold.
  • Human (Homo sapiens)peptidylprolyl cis/trans isomerase [PDB 1VBS] (class: all-β). The dominant feature of the structure is a β-sandwich fold.
  • Cow (Bos taurus) γ crystallin [PDB 1A45] (class: all-β) This protein contains β-barrel two domains.
  • Jellyfish (Aequorea victoria) green fluorescent protein [PDB
    1GFL
    ] (class: all-β). This is a β-barrel structure with a central α helix. The strands of the sheet are antiparallel.
  • Pig (Sus scrofa) retinol-binding
    protein [PDB 1AQB] (class: all-β). Retinol binds in the interior of a β-barrel fold.
  • Brewer’s yeast (Saccharomyces carlsburgensis) old yellow enzyme
    (FMN oxidoreductase) [PDB 1OYA] (class: α/β). The central fold is an α/β barrel with parallel β strands connected by α helices. Two of the connecting regions are highlighted in yellow.
  • Escherichia coli enzyme required for tryptophan biosynthesis [PDB 1PII] (class: α/β). This is a bifunctional enzyme containing two distinct domains. Each domain is an example of an α/β barrel. The left-hand domain contains the indolglycerol phosphate synthetase activity, and the right-hand domain contains the phosphoribosylanthranilate isomerase activity.
  • Pig (Sus scrofa) adenylyl kinase [PDB 3ADK] (class: α/β). This single-domain protein consists of a five-stranded parallel β sheet with layers of α helices above and below the sheet. The substrate binds in the prominent groove between helices.
  • Escherichia coli flavodoxin [PDB 1AHN] (class: α). The fold
    is a five-stranded parallel twisted sheet surrounded by α helices.
  • Human (Homo sapiens) thioredoxin [PDB 1ERU] (class: ). The structure of this protein is very similar to that of E. coli flavodoxin except that the five-stranded twisted sheet in the thioredoxin fold contains a single antiparallel strand.
  • Escherichia coli L-arabinose-binding protein [PDB 1ABE] (class: α/β). This is a two-domain protein where each domain is similar to
    that in E. coli flavodoxin. The sugar L-arabinose binds in the cavity between the two domains.
  • Escherichia coli DsbA (thiol-disulfide oxidoreductase/disulfide isomerase) [PDB 1A23] (class: α/β). The predominant feature of this structure is a (mostly) antiparallel β sheet sandwiched between α helices. Cysteine side chains at the end of one of the α helices are shown (sulfur atoms are yellow).
  • Neisseria gonorrhea pilin [PDB 2PIL] (class: α + β). This polypeptide is one of the subunits of the pili on the surface of the bacteria responsible for gonorrhea. There are two distinct regions of the structure: a β sheet and a long α helix.
  • Chicken (Gallus gallus) triose phosphate isomerase [PDB 1TIM]. This protein has two identical subunits with α/β barrel folds.
  • HIV-1 aspartic protease [PDB 1DIF]. This protein has two identical all-β subunits that bind symmetrically. HIV protease is the target of many new drugs designed to treat AIDS patients.
  • Streptomyces lividans potassium channel protein [PDB 1BL8]. This membrane-bound protein has four identical subunits, each of which contributes to a membrane-spanning eight-helix bundle.
  • Bacteriophage MS2 capsid protein [PDB 2MS2]. The basic unit of the MS2 capsid is a trimer of identical subunits with a large β sheet.
  • Human (Homo sapiens) hypoxanthine-guanine phosphoribosyl transferase (HGPRT) [PDB 1BZY]. HGPRT is a tetrameric protein containing two different types of subunit.
  • Rhodopseudomonas viridis photosystem [PDB 1PRC]. This complex, membrane-bound protein has two identical subunits (orange, blue) and two other subunits (purple, green) bound to several molecules of photosynthetic pigments.


Horton, H.R., Moran, L.A., Scrimgeour, K.G., perry, M.D. and Rawn, J.D. (2006) Principles of Biochemisty. Pearson/Prentice Hall, Upper Saddle River N.J. (USA)

Levels of Protein Structure

There are four levels of protein structure. The primary structure refers to the sequence of amino acid residues in the polypeptide chain written left-to-right from the N-terminus to the C-terminus.

Secondary structures are ordered structures formed by internal hydrogen bonding between amino acid residues. The common secondary structures are the α helix, the β strand, and various loops and turns. The β sheet is often counted as secondary structure although, strictly speaking, it is a motif (see below).


The tertiary structure of a polypeptide is the three-dimensional conformation. Typical proteins contain α helices, β strands, and turns, although there are some proteins that only have α helices and turns, and others that have only β sheets and turns. In many cases, the final structure consists of distinct, independently folded regions called domains.

An example of a protein with multiple domains is shown on the left. This protein is the enzyme pyruvate kinase from cat (Felix domesticus). There are three separate domains indicated by the square brackets on the side. Note that each of the domains is connected to another by a short stretch of unordered polypeptide chain.

In some cases, a particular domain is shared by several proteins suggesting that different proteins can be formed by combining various domains that evolved separately. In other cases, similar domain structures might arise independently by convergent evolution.

Quaternary structure only applies to proteins that are composed of more than one polypeptide chain. Each of the polypeptides is called a subunit. The subunits might be identical, as in the example shown above, or they might be very different as in my favorite enzyme ubiquinone:cytochrome c oxidoreductase (complex III).

There are certain motifs that occur over and over again in different proteins. The helix-loop-helix motif, for example, consists of two α helices joined by a reverse turn. The Greek key motif consists of four antiparallel β strands in a β sheet where the order of the strands along the polypeptide chain is 4, 1, 2, 3. The β sandwich is two layers of β sheet [see β Strands and β Sheets].

The vast majority of motifs do not have a common evolutionary origin in spite of many claims to the contrary. They arise independently and converge on a common stable structure. The fact that these same motifs occur in hundreds of different proteins indicates that there are a limited number of possible folds in the universe of protein structures. The original primitive protein may have been relatively unstructured but over time there will be selection for more and more stable structures. This selection will favor the common motifs.

Larger motifs are often called domain folds because they make up the core of a domain. The parallel twisted sheet is found in many domains that have no obvious relationship other than the fact that they share this very stable core structure. The β barrel structure is found in many membrane proteins. There are dozens of enzymes that have adapted to an α/β barrel. These enzymes are not evolutionarily related. (The β helix is much less common.)


[Figure Credit: The figures are from Horton et al. (2006)]

Horton, H.R., Moran, L.A., Scrimgeour, K.G., perry, M.D. and Rawn, J.D. (2006) Principles of Biochemisty. Pearson/Prentice Hall, Upper Saddle River N.J. (USA)

Loops and Turns

In addition to α helices and β strands, a folded polypeptide chain contains two other types of secondary structure called loops and turns. (There are also regions of unordered structure, often called coils.)

Loops and turns connect α helices and β strands. The most common types cause a change in direction of the polypeptide chain allowing it to fold back on itself to create a more compact structure.

Loops are not well defined. They generally have hydrophilic residues and they are found on the surface of the protein. Loops that have only 4 or 5 amino acid residues are called turns when they have internal hydrogen bonds. Reverse turns are a form of tight turn where the polypeptide chain makes a 180° change in direction. Reverse turns are also called β turns because they usually connect adjacent β strands in a β sheet.

Reverse turns. (left) Type I β turn. The structure is stabilized by a hydrogen bond between the carbonyl oxygen of the first N-terminal residue (Phe) and the amide hydrogen of the fourth residue (Gly). Note the proline residue at position n + 1 (right) Type II β turn. This turn is also stabilized by a hydrogen bond between the carbonyl oxygen of the first N-terminal residue (Val) and the amide hydrogen of the fourth residue (Asn). Note the glycine residue at position n + 2 [PDB 1AHL (giant sea anemone neurotoxin)]. (Horton et al. 2006)
The two most common common types of β turn are the type I and type II turns shown above. The key point about turns is that they are highly ordered structures stabilized by internal hydrogen bonds. This is why they are counted as the third form of secondary structure (along with the α helix and β strand).


Horton, H.R., Moran, L.A., Scrimgeour, K.G., perry, M.D. and Rawn, J.D. (2006) Principles of Biochemisty. Pearson/Prentice Hall, Upper Saddle River N.J. (USA)

Wednesday, March 12, 2008

Nobel Laureates: Sir William Henry Bragg and Lawrence Bragg

 

The Nobel Prize in Physics 1915.

"for their services in the analysis of crystal structure by means of X-rays"


In 1915, Sir William Henry Bragg (1862 - 1942) and William Lawrence Bragg (1890 - 1971) were awarded the Nobel Prize in Physics for their work on the structure of crystals as determined by X-ray crystallography. The Physics prize in 1914 had been awarded to Max von Laue for his discovery of the diffraction of X-rays by crystals.

In order to solve the structure of a crystal, two advances were necessary. First, the senior Bragg developed an X-ray spectrometer that produced a monochromatic (single frequency) beam of X-rays of the desired strength. Second, his son Lawrence, worked out the mathematics of the diffraction in order to relate the pattern of diffraction images to the underlying structure. Part of this solution is the Bragg Equation or Bragg's Law.

After World War II, William Lawrence Bragg (then Sir Lawrence Bragg) became head of the Cavendish Laboratory in Cambridge. He rapidly transformed the laboratory into a center or the study of biological molecules. Bragg was responsible for hiring several future Nobel laureates including Max Perutz, John Kendrew, and Fred Sanger. Francis Crick and Jim Watson were also part of this group [see The Storyof DNA: Part 1].

The Braggs were the first Australians to win Nobel Prizes. Lawrence Bragg was the youngest person to win a Nobel Prize (he was 25 years old in 1915). The Braggs are the only father and son team to share a Nobel Prize. (Can anyone name the other parent/sibling pair(s) to win separate Nobel Prizes?)

The presentation speech was delivered by Professor G. Granqvist, Chairman of the Nobel Committee for Physics of the Royal Swedish Academy of Sciences.
THEME:

Nobel Laureates
Von Laue's epoch-making discovery of the diffraction of the X-rays in crystals, on the one hand established wave motion as the essential quality of those rays and, on the other, afforded the experimental proof of the existence of molecular gratings in the crystals. The problem, however, of calculating the crystal structures from von Laue's formulae was an exceedingly complicated one, in as much as not only the space lattices, but also the wavelengths and the intensity-distribution over the various wavelengths in the spectra of the X-rays, were unknown quantities. It was consequently a discovery of epoch-making significance when W.L. Bragg found out that the phenomenon could be treated mathematically as a reflection by the successive parallel planes that may be placed so as to pass through the lattice points, and that in this way the ratio between the wavelengths and the distances of the said planes from each other can be calculated by a simple formula from the angle of reflection.

It was only by means of that simplification of the mathematical method that it became possible to attack the problem of the crystal structures, but to attain the end in view it was further necessary that the photographic method employed by von Laue should be replaced by an experimental one, based on the reflection principle, which admitted of a definite, even though at first unknown, wavelength being made use of. The instrument requisite for the said purpose, the so-called X-ray spectrometer, was constructed by Professor W.H. Bragg, W.L. Bragg's father, and it has been with the aid of that instrument that father and son have carried out, in part conjointly, in part each on his own account, a series of extremely important investigations respecting the structure of crystals.

If a number of cubes are laid on and beside each other in such a way that one cube face coincides in every case with the face of an adjoining cube, whereby consequently eight vertices always meet in one point, those angular points give a visual picture of the lattice points in the so-called simple cubic lattice. If again a lattice point is placed so as to coincide with the central point of each cube face, the so-called face-centred cubic lattice is obtained, whereas the centred cubic lattice has one lattice point in every cube-centre. With the exception of these three cases there is no cubic lattice that fulfils the condition that parallel planes placed in any direction whatever so as to pass through all the lattice points, shall also be at a constant distance from each other. The space lattice in the regular or cubic system must therefore coincide with one of those three, or constitute combinations of them. In such lattice combinations, on the other hand, in which the condition just mentioned is not fulfilled, where consequently parallel planes placed to pass through all the lattice points in certain directions are not equidistant, that circumstance is revealed by an abnormal intensity distribution among spectra of different orders, when the reflection takes place by those planes.

From crystallographical data it is always known how the face of a cube is situated in any given regular crystal, and there is consequently no difficulty in fixing the crystal on the spectrometer table in such a way that the reflection shall take place by planes with any prescribed orientation.

The rays falling on the crystal were produced by X-ray tubes, platinum being at first used for the anticathode. The characteristic X-radiation of the metals consists, as is well known, of a few strong lines or narrow bands, and the very first experiments with the spectrometer revealed the X-radiation that is characteristic of platinum. However, in the research undertaken to find out the nature of complicated space lattices, in which an abnormal intensity distribution among spectra of varying orders constitutes one of the most important of the results observed, it soon proved desirable to have available an X-radiation of approximately half the wavelength of the strongest platinum-line. From theoretical considerations W.H. Bragg regarded it as probable that a metal whose atomic weight was somewhere near the figure 100, would give a characteristic radiation of the desired wavelength. Accordingly anticathodes of palladium and rhodium were produced, which fully answered the purpose in view, so that spectra ev en of the fifth order could be obtained and measured. In order to take practical advantage, however, of those results, it was essential to have a method for calculating the intensity in the case of a complicated space lattice, that would prove simpler than the one given by von Laue's theory, and W.L. Bragg developed one.

The above is a brief sketch of the methods discovered by the two Braggs for investigating crystal structures. The results of their investigations embrace a large number of crystals belonging to various systems and can only be cursorily summarized in this place.

To begin with, the two investigators applied themselves to the simplest types of the regular system, represented by the alkaline haloid salts. It then proved that potassium bromide and potassium iodide showed the spectra that are characteristic of a face-centred cubic lattice, while the spectra of potassium chloride represented a simple cubic lattice, sodium chloride occupying an intermediate position. As it must be assumed, on the strength of the analogy of these salts, both in a chemical and a crystallographical sense, that they are possessed of a corresponding space lattice, which could also be corroborated in another way, it was proved by those researchers that the lattice of the crystals in question consists of two face-centred cubic lattices corresponding to the two atoms, which interpenetrate in such a way that they together constitute one single cubic lattice.

From these investigations it follows that a metal atom in the crystals of the alkaloid salts is situated at one and the same distance from the six haloid atoms nearest to it, and vice versa - a relationship that was found to prevail, mutatis mutandis, in all the crystals examined. That means the exceedingly important discovery, both for molecular physics and chemistry, that the crystals consist of atomic lattices and not, as has been always imagined, of molecular ones.

Two face-centred cubic lattices can also interpenetrate in such a way that every point belonging to the one lattice is at the centre of gravity of a tetrahedron whose vertices are points belonging to the other lattice. That structure was found by the two Braggs in the diamond, and afforded an experimental support for the tetrahedral arrangement that chemists postulate for the four-coordinate carbon. On the other hand, the explanation became evident of why crystallographers have not been able to agree regarding the class in the regular system to which the diamond should be referred.

It would carry us too far and be quite too complicated a proceeding to give an account here of the further investigations into the space lattices of the crystals. It will suffice to add that, in the course of their investigations, the two Braggs have also discovered important relations between the amplitude and the phase difference of the diffracted rays on the one hand and the atomic weights on the other, and have also shown experimentally the influence of heat on the space lattice.

Finally it may be mentioned that the two investigators have also determined the wavelengths of the X-rays and the distances between the successive planes placed to pass through the lattice points with such exactitude, that the error, if any, is probably a t most some few units per cent and is more due to the general physical constant entering into the calculations than to the measurements themselves.

Thanks to the methods that the Braggs, father and son, have devised for investigating crystal structures, an entirely new world has been opened and has already in part been explored with marvellous exactitude. The significance of these methods, and of the results attained by their means, cannot as yet be gauged in its entirety, however imposing its dimensions already appear to be. In consideration of the great importance that these methods possess for research in the realm of physics, the Swedish Royal Academy of Sciences decided that the 1915 Nobel Prize in Physics should be divided between Professor W.H. Bragg and his son W.L. Bragg, in recognition of their services in promoting the investigation of crystal structures by means of X-rays.