Heat Shock and Molecular Chaperones

 
Protein folding takes place inside cells at their normal temperature. This temperature is 37°C in the case of mammals. If cells encounter higher temperatures, their proteins become unfolded since the minimal energy conformation at one temperature isn't the same minimum at a another temperature.

The difference in temperature isn't large. Many mammalian proteins become unstable at 42°C. This is a temperature encountered with high fever but it's also common in skin cells that have been exposed to the sun or the water in a hot tub. Temperature differences are even more common in species that do not regulate their temperature (e.g., plants, fungi, bacteria, invertebrates).

All living cells have defense mechanisms that protect against exposure to high temperature. They produce special proteins called heat shock proteins in order to recover damaged proteins that have unfolded at the high temperature. Many of the heat shock proteins are molecular chaperones. These are proteins that guide proper refolding of damaged proteins.

Shortly after the discovery of heat shock proteins we learned that these proteins are always present even in cells that haven't been stressed. In other words, molecular chaperones play a role in normal protein folding as well as helping to recover from damage. This role is illustrated in the energy diagram (top left).

One of the pathways to the energy minimum follows the line labeled "B." This traverses a local energy well and proteins can get trapped in this pit. What happens is that they adopt a less-than-optimal conformation but they can't easily unfold and refold to fall down into the deeper well because that would require an increase in energy. It will happen eventually, but it could take a long time. Chaperones help direct folding along the proper pathway and his speeds up the folding process.

Recall from the earlier discussion of How Proteins Fold that folding is an entropy-driven process where the end result is to bury hydrophobic residues in the central core of the protein. Another thing that can happen during folding is that exposed hydrophobic surfaces of one protein can interact with similar surfaces in another protein leading to aggregation. Chaperones can bind to these hydrophobic surfaces and prevent aggregation. This is another way of speeding up folding.

There are many different chaperones. My personal favorite is HSP70 (Heat Shock Protein of relative molecular mass 70,000). This is a protein that's found in every type of living species. It is the most highly conserved protein in all of biology so it's an excellent protein for looking at deep phylogeny. The role of HSP70 as a molecular chaperone is to bind to proteins as they are being synthesized in order to prevent improper folding. It also prevents aggregation.

Another famous chaperone used to be called HSP60 since it was a heat shock protein of M_r= 60,000. It was also known as GroE since it allowed for the growth of bacteriophage λ gene E mutants. Now it's known as chaperonin. Note that the term "chaperonin" refers to a specific molecular chaperone.

Chaperonin is a barrel-shaped molecule consisting of two rings of seven subunits surrounding a central cavity (one subunit is colored green in the image) . The top of the cavity is sealed by cap of seven smaller subunits. The chaperone works by capturing small unfolded proteins in the cavity where the hydrophobic environment encourages rapid folding to the correct conformation. Aggregation is also prevented by keeping the folding protein away from other proteins.

The inside of the cavity is referred to as an Anfinsen cage after Christian Anfinsen, a Nobel Laureate who worked on protein folding (see next Wednesday's Nobel Laureate). The release of unfolded protein is coupled to the hydrolysis of ATP. This is a common feature of most molecular chaperones.

Daniel vs the Christians

Let me make it clear that I'm not a fan of Daniel Dennett. I think his version of evolution is sophomoric and wrong. His book "Darwins' Dangerous Idea" was one of the worst books on evolutionary theory that has ever been published.

Nevertheless, from time to time Dennett gets things right. One of those times was in the New York Review of Books last month where he took on Allen Orr [letter from Daniel Dennett].

You might recall the kerfuffle over Orr's review of The God Delusion. Orr claimed that Dawkins had ignored all the more sophisticated arguments for the existence of God. Here's part of Dennett's reply,

H. Allen Orr, in "A Mission to Convert" [NYR, January 11], his review of Richard Dawkins's The God Delusion and other recent books on science and religion, says that Dawkins is an amateur, not professional, atheist, and has failed to come to grips with "religious thought" with its "meticulous reasoning" in any serious way. He notes that the book is "defiantly middlebrow," and I wonder just which highbrow thinkers about religion Orr believes Dawkins should have grappled with. I myself have looked over large piles of recent religious thought in the last few years in the course of researching my own book on these topics, and I have found almost all of it to be so dreadful that ignoring it entirely seemed both the most charitable and most constructive policy. (I devote a scant six pages of Breaking the Spell to the arguments for and against the existence of God, while Dawkins devotes roughly a hundred, laying out the standard arguments with admirable clarity and fairness, and skewering them efficiently.) There are indeed recherché versions of these traditional arguments that perhaps have not yet been exhaustively eviscerated by scholars, but Dawkins ignores them (as do I) and says why: his book is a consciousness-raiser aimed at the general religious public, not an attempt to contribute to the academic microdiscipline of philosophical theology. The arguments Dawkins exposes and rebuts are the arguments that waft from thousands of pulpits every week and reach millions of television viewers every day, and neither the televangelists nor the authors of best-selling spiritual books pay the slightest heed to the subtleties of the theologians either.

Who does Orr favor? Polkinghorne, Peacocke, Plantinga, or some more recondite thinkers? Orr brandishes the names of two philosophers, William James and Ludwig Wittgenstein, and cites C.S. Lewis's Mere Christianity, a fairly nauseating example of middle-brow homiletic in roughly the same league on the undergraduate hit parade as Lee Strobel's The Case for Christ (1998) and transparently evasive when it comes to "meticulous reasoning." If it were a book in biology—Orr's discipline—I daresay he'd pounce on it like a pit bull, but like many others he adopts a double standard when the topic is religion....

[Hat Tip: [RichardDawkins.net]

Sylvia Browne Is a Fraud

 
The so-called psychic Sylvia Browne is a fraud. There's a website called stopsylviabrowne devoted to exposing her. Recently Sylvia Browne's lawyers tried to shut down the website but the owner wasn't cowed. He got his own lawyers to fight back. You should see the letter they sent to Sylvia Browne's lawyers. Read it [here].

Delicious.

[Hat Tip: The Bad Astronomer]

The Separation of Church and State

John Pieret and I have often argued about religion and science. He is a classic appeaser even though he doesn't support any of the established religions. John notes that this is the anniversary of a famous court decision in America [Madison's Avenue].

John list ten "rules" concerning the separation of church and state. I thought I might respond to those rules in the context of a non-American. It will be interesting to see if there's a difference in how Americans perceive "separation of church and state" and how it's perceived in other countries.

John's rules are in boldface and my response are in italics.

10 Commandments of the Separation of Church and State:

1. Neither a state nor the Federal Government can set up a church.

I disagree in the sense that many countries with a state church don't seem to have as the same problems as the USA. So, I would not advocate a hard and fast rule that forbids state religions. I don't think a modern country should set up a new state religion but neither do I think that existing ones need to be abolished. I would definitely support disestablishment, myself, but antidisestabishmentarianism shouldn't be illegal.

2. Neither a state nor the Federal Government can pass laws which aid one religion, aid all religions, or prefer one religion over another.

I disagree with this as well. There's nothing seriously wrong with tax breaks for religious charities, for example and there's nothing wrong with laws that proclaim national holidays on days with special religious significance for one group. (e.g., Good Friday) I prefer to live in a society that chooses not to favor religions but it shouldn't be illegal.

3. Neither a state nor the Federal Government can force nor influence a person to go to or to remain away from church against his will.

Nobody disagrees with the "force" part but the "influence" part is a different story. I favor a government that influences people to stay away from churches that preach hatred and bigotry.

4. Neither a state nor the Federal Government can force a person to profess a belief or disbelief in any religion.

Everyone agrees with this one.

5. No person can be punished for entertaining or professing religious beliefs.

I agree in principle. There might be some extreme cases of religions that merit banning but these are exceptions. In a case where one's religious beliefs might case harm (e.g., refusing blood transfusions for children) the state is justified in stepping in even though this can easily be seen as punishment.

6. No person can be punished for entertaining or professing religious disbeliefs.

This one seems pretty straightforward. It's the one that's most difficult to enforce, however. Right now atheists would have a very hard time getting elected in many parts of the USA.

7. No person can be punished for church attendance or non-attendance.

Same as #5.

8. No tax in any amount, large or small, can be levied to support any religious activities or institutions, whatever they may be called, or whatever form they may adopt to teach or practice religion.

I disagree. Tax money is used to support religious schools in Canada and many European countries. While I would argue strongly against such a practice, I see no reason to make it against the law. It's a matter for society to decide, not the courts.

9. Neither a state nor the Federal Government can, openly or secretly, participate in the affairs of any religious organizations or groups.

Lots of countries have state religions. In modern civilized countries, they're pretty harmless for the most part. I don't see any reason to have a constitutional amendment in Great Britain.

10. No religious organizations or groups can, openly or secretly, participate in the affairs of a state or the Federal Government.

Same response as #9.

What a Surprise!

 

You are 100% atheist!

 

Hooray you are an atheist with respect to most or all gods. Good work. Hope you aren't disbelieving in the wrong one...

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All Seven Continents

 
I was just checking to see where you all were coming from when I realized that in the past few hours I've had visitors from all seven continents!!!

Isn't that amazing? (I'm pretty sure there are Sandwalk readers in Antarctica—you just can't see the white dots against the snow.)

Uncommon Descent Supports Bigots

 
Considering the mess that Paula Zhan has created, you'd think the Intelligent Design Creationists wouldn't touch it with a ten foot pole. After all, they don't want to be seen defending bigots, do they?

Yep, they do. Bashing atheists and Muslims is just too much for DaveScot to resist [Karen Hunter and Debbie Schlussel - YOU GO, GIRLS!].

(I think I've figured it out. The best way to predict how the IDiots are going to behave is to assume they'll do the stupidist thing you can imagine.)

Here's the original show—the one that impressed DaveScot. Watch the followup tonight when Paula Zhan interviews Richard Dawkins. Given Paula's track record I'm predicting that she will look very stupid foolish. I'm betting the IDiots are gonna love it.

The IDiots Don't Under stand Irreducible Compexity

 
Evolution News & Views, the Intellgent Design website, has just posted a quotation from a Professor of Design and Nature(?) at Bristol University in the UK.

I've been designing systems like spacecraft for more than 20 years. One of the lessons I've learnt is that complex systems require an immense amount of intelligence to design. I've seen a lot of irreducible complexity in engineering. I have also seen organs in nature that are apparently irreducible. An irreducibly complex organ is one where several parts are required simultaneously for the system to function usefully, so it cannot have evolved, bit by bit, over time.

I thought that by now even the IDiots would know that irreducibly complex systems can arise by evolution. Apparently I was wrong. The IDiots haven't been paying attention to anything that scientists have been saying over the past 15 years.

I guess that's why they're IDiots.

American Museum of Natural History

 
The American Museum of Natural History has just opened its new exhibit on human origins (see The New York Times). PZ Myers notes a paragraph in the article about balancing religion and science,

One issue cannot be entirely sidestepped in any public presentation of human evolution: that many people in this country doubt and vocally oppose the very concept. In a corner of the hall, several scientists are shown in video interviews professing the compatibility of their evolution research with their religious beliefs.

Fine, I understand why this might be considered necessary in a science museum but shouldn't the other side be presented as well? After all, most scientists are non-believers.

Why not have a video presentation of atheist scientists who point out the conflicts between science and religion? Why not present the reasons why evolutionary biology is incompatible with many religious beliefs?

I wonder which "scientists" are featured in the presentation? Do you suppose it's the usual suspects like Ken Miller and Francis Collins or are there some Hindus, Muslims, Jews, and Buddhists as well?

Toronto City Council

 
Last Tuesday the Toronto City Council met for their annual photo. Several of the more senior—and more conservative—councillors were upset because they couldn't sit in the first row, which was reserved for the Mayor and the Executive Committee.

The squabbling persisted for so long that the photo shoot had to be canceled. I love the cartoon in today's Toronto Star and I just can't resist posting a copy. It captures the mood exactly. (It also reminds me of the Discovery Institute.)

Tuition

 
Hundreds of students turned out yesterday for a rally at Queen's Park (Ontario Parliament Buildings). Many of the students marched from the University of Toronto campus and they waited in the freezing cold for more than an hour before the contingent from Ryerson marched along College St. and up University Ave. to join them.

Like most Professors, I want tuition to be as low as possible because education is a right. The government of Ontario should at the very least hold the current tuition at its present level for the foreseeable future. It should increase direct funding to the universities to maintain quality and allow for expansion.

The long-term goal should be to provide free education to all qualified students.

How Proteins Fold

The protein shown here is pyruvate kinase, one of the key enzymes in metabolism. This particular example comes from the common domestic cat (Felix domesticus).

Cartoons such as this one are intended to show how the backbone chain of amino acids is folded to produce the final three-dimensional structure of a protein. In this case the polypeptide chain is represented by a blue ribbon. There are spiral sections representing regions of secondary structure called α-helices and flattened sections called β-strands. The β-strand regions are often twisted.

This particular protein adopts a structure with three distinct parts called domains. As a general rule, each domain has a well-defined shape with a characteristic pattern of strands and helices. The pattern is called a fold and it it thought that there are only 1000 or so different folds in the protein universe. Different folds can be combined to make up all known proteins.

(For those who might be interested, the three domain folds in this protein are TIM beta/alpha barrel, PK beta-barrel, and the PK C-terminal domain.)

When proteins are first synthesized you can think of them as a long extended chain of amino acids with no particular secondary or tertiary structure. We refer to such unordered macromolecules as random coils. Within seconds, this random coil spontaneously folds itself into a highly ordered three-dimensional structure such that every single molecule of a given protein has the exact same shape. For example, every molecule of pyruvate kinase looks exactly like the one shown here.

The rapidity of this folding reaction tells us something about the mechanism of protein folding. We know that folding is rapid and spontaneous because proteins can be purified then unfolded by treating them with certain chemicals that cause them to become denatured or unfolded. These denatured proteins can then be allowed to re-fold when the chemicals are removed.

Cyrus Levinthal did some back-of-the-envelope calculations on the rate of protein folding. He assumed that a protein could randomly try all possible three-dimensional conformations until it found the correct one. Under those conditions it would take 10⁸⁷ seconds to fold a protein of 100 amino acid residues. This is quite a bit longer than the age of the universe (6 x 10¹⁷ seconds).

Obviously, there's something wrong with the assumptions behind what came to be known as the Levinthal Paradox. As a matter of fact, the paradox was never really a paradox since the whole point of the calculation was to shown that proteins did not fold by randomly searching though the conceptual universe of all possible shapes.

The final structure of a protein minimizes the energy of the random coil by burying hydrophobic amino acids in the interior of the molecule. Hydrophobic (water fearing) amino acids are those that don't like to be exposed to water. Just as scattered oil droplets in your salad dressing will eventually coalesce to form a layer of oil over a layer of vinegar and water, so too will hydrophobic amino acids come together to form an "oily" globule in the middle of the protein. Water is excluded from this "molten globule" and this makes folding an entropically driven spontaneous reaction.

You can visualize the process by picturing a field of all possible energy levels of the random coil. The one representing the properly folded protein is the deepest well on the energy surface. The bottom of the well is the lowest energy level for the protein and this represents the stable three-dimensional structure. Protein folding, then, is like finding the well and falling down into it.

As mentioned above, the search for the lowest energy well is not a random search of all possible shapes. That would take far too long. Instead, folding proceeds in a cooperative stepwise manner with small regions of secondary structure forming first.

The most striking regions of secondary structure are the short α-helices. Certain stretches of amino acid residues will rapidly form α-helical regions involving local bonding between amino acids. These form extremely rapidly since the amino acids are already in close contact. Furthermore, the formation of these local secondary structures takes place simultaneously in many different parts of the random coil.

The helix and strand regions represent the minimal energy conformations of the local parts of the protein. Subsequent folding proceeds by forming the helices and strands into the appropriate three-dimensional folds that are characteristic of each domain. The possibilities here are much fewer than the total of all possible conformations because you are now combining blocks of amino acids that have already adopted some structure.

The figure below shows some hypothetical examples of folding pathways. Very few folding pathways have been worked out in detail but the basic principles are well understood. The biggest unsolved problem is predicting the three-dimensional structure of a protein from its amino acid sequence. This involves finding the predicted lowest energy level and that's turning out to be a tough problem indeed.

IDiot "Irony"

 
GilDodgen is one of the IDiots who post regularly to Uncommon Descent. Recently he put up a comment on a photo of Darwin's tomb that I posted one month ago. GilDodgen thought he was being so clever that he re-posted his comment in an article on Uncommon Descent [Darwin’s Final “Resting” Place]. Here's what he said,

Over at Larry Moran’s blog, where I am identified as one of the ID movement’s stellar idiots, there is a picture of Darwin’s tombstone with the caption: “Here’s a photo of Darwin’s final resting place in Westminster Abbey.”

I posted the following comment:

Darwin doesn’t have a resting place. When he died he entered eternal oblivion. Nothing he did, and nothing that any of us do, has any lasting significance or meaning.

One day our sun will turn into a red giant. When that happens its corona will expand beyond the orbit of the earth. The earth’s atmosphere will be stripped away, the seas will boil away, the sands will fuse into glass, and all life will be exterminated. There will be no record of anything anyone has ever done, created, or thought.

For those familiar with me at UD, the irony should be self-evident.

Guess what? The "irony" isn't self-evident to me. I'm not really sure what the fuss is about. Are they objecting to the phrase "final resting place" on the grounds that Darwin's soul will survive? Is he thinking that Darwin will never rest because he has to suffer forever for his heretic views? Or is it something else that I'm missing?

I dunno, so I did the normal thing and posted a question on Uncommon Descent—forgetting that I am persona non grata over there. Naturally my comment never made it past the IDiot censors. Can someone help me out? What's the problem?

As you might expect, the readers at UD are falling all over themselves in support of the clever, ironic comment by GilDodgen. For example, scordova posted the following comment at Uncommon Descent.

Gil, I noticed you pointed out your professional credentials to Moran. Actually, imho, when people like Moran are knocked off of their elistist horse by a lowly peasant, it’s a more satisfying victory. It’s more fun when people like Moran get taken out by people they view as their inferior….

"Taken out"? I was? Hmmm ... I must have missed the take out.

Incidently, I'm unaware of the "professional credentials" of GiDodgen. All I know is that he doesn't understand science and that makes him look pretty stupid. I suppose that's a form of "professional credential."

GilDodgen replied,

Good point. However, in the case of Moran, he thinks that anyone who doubts Darwin is a rube and a simpleton who should be flunked out of college for no other reason. He should be made aware that it is possible to doubt Darwin and still be capable of rational, logical thought.

Oh dear. The IDiots reveal once again that they are incapable of distinguishng between Darwinism and evolution. I have lots of doubts about the validity of Darwinism as a complete explanation of evolution and I haven't been the least bit shy about expressing those doubts.

People who doubt the exclusive role of natural selection are not rubes or simpletons. People who don't understand the real meaning of Darwinism are rubes and simpletons. There are tons of them over at Uncommon Descent.

"IDiots" is my special scientific term for those people who are anti-evoluton and anti-science. GilDodgen and scordova are IDiots. The fact that they are also rubes and simpletons is simply a nice bonus.

Flock of Dodos and Haeckel's Embryos

 
Randy Olson made a movie called Flock of Dodos where he pokes fun at the IDiots. Unfortunately, Olson made a mistake when he said that the old faked images of Haeckel's embryos were not in modern textbooks.

The Discovery Institute pounced on this error and made a clever video that discredits Olson. The DI video may have some errors of its own; for example, I'm not sure if the embryo picture in the Raven & Johnson biology textbook is actually based on a Haeckel drwaing as they say. Also, the picture of the Haeckel woodcut in the Alberts texbook isn't as significant as they imply.

In spite of the possible mistakes in the video (below) the DI has been quite clever. The IDiots have cast doubt on all the claims in Flock of Dodos because of one little slip-up.

Debbie Schlussel

 
UPDATE: PZ Myers tells us that CNN will rebroadcast the segment tonight at 8PM EST with a new panel, including Richard Dawkins (CNN must have felt the heat).

Do you remember Debbie Schlussel? She was the atheist-hating Jewish idiot who appeared on the Paul Zahn show last week (see Paula Zhan Should be Fired from CNN). Readers might recall that I was wondering whether Schlussel might have a slight bias against Muslims as well as atheists.

Well, it turns out Debbie Schlussel has been receiving emails about her remarks on CNN (Duh!). She has a blog where she has just confirmed our worst fears.

Here's part of what she says at "When Atheists a/k/a Future Muslims Attack."

I don't mind receiving the atheist hate mail, since I know that in a few years, many of these same people will either be Muslim extremists (redundant) or helping the country fall further in its fight against the creep of Islamic imposition on America . . . or both.

Look at famous atheists and what happened to them. Adam Gadahn a/k/a Azzam Al-Amriki--now a top Al-Qaeda video "personality"--was raised by his hippie Jewish father and equally bizarre gentile mother as an atheist. And look how he turned out. Ditto for hippie-spawn John Walker Lindh.

Those two people are enemies of America, and many of those who think like them are of equally weak mind. If you don't believe in anything, you'll easily fall for virtual nothings. That's why Europe is so quickly turning Islamist--because atheism dominates and Christianity is rapidly dying there. Over there, the number one cause for which atheists are suddenly finding "god" is Islam.

No, your eyes aren't deceiving you. She actually said that on her blog. Go check it out if you don't believe me. She's a genuine loony nutcase.

All the more reason why Paula Zhan should stop pretending to be a journalist.

On her blog Schussel attacks those critics who claim they just saw the Paula Zhan show.

It's hard to believe their letters because they were all attacking me for my appearance on CNN's "Paula Zahn Now," a week ago, but coincidentally each letter claims the sender just watched me on CNN. First of all, the video of that segment appears nowhere on the net. Believe me, if it did, I'd link to it.

I linked to the videos on the net and so have dozens of other bloggers who are astonished at the stupidity of CNN. It looks like Schlussel is incompetent at many different things in addition to thinking logically. Her list of failings includes searching the internet.

Read the posting on Dr. Joan Bushwell's Chimpanzee Refuge [Debbie Schlussel: A case study in 15 minutes too many] for a calmer attack on Debbie Schussel. Schlussel is a journalist who's greatest achievement to date was winning the title of "Outstanding Teen Age Republican in the Nation" in 1987 (Wikipedia). Why is it that so many kooks seem to be Republicans?

[Hat Tip: Friendly Atheist]