I don't know if I have linked to this paper before, but if I haven't I definitely should. It's a seminal Science paper by Frank Westheimer in which he describes his thoughts on why nature chose phosphates as the most important signaling and building blocks in living organisms.
The entire paper is eminently readable and among other things, Westheimer compares the properties of phosphates with other possible groups such as arsenates and sulfates. Basically the bottom line is that phosphates possess the right value of pKa to be doubly ionized at physiological pH. The singly ionized form in the phosphodiester linkages of nucleic acids prevents the group from being easily hydrolyzed from nucleophilic attack by water, without making the group so stable that it won't undergo enzymatic hydrolysis.
As in other chemical schemes that Nature has developed, it's the right combination of stability and lability that makes phosphates ideal for being among the most fundamental chemical entities in life's inventory. And all essentially because of the right acid-base chemistry of phosphoric acid.
Hexacyclinol: Case Closed
Seems that hexacyclinol is finally dead and buried and the tomb has been sealed. If anyone had any doubt that there was something wrong with the original structure, this paper should resolve it. For those who have had the good fortune of not hearing about hexacyclinol, see the links at the end.
In any case, the present authors from Italy simply calculate H1 chemical shifts and coupling constants for the original disputed structure (1) and the newly proposed and calculated structure (2). Recall that one of the things James La Clair claimed when John Porco synthesized what Scott Rychnovsky felt (Yes, it does sound like one of those convoluted Shakespearean chains of people) was the correct structure was that the two different structures could possibly give rise to the same or extremely similar NMR spectra.
Yes, it's probably true that in the infinitely large universe of organic compounds one could possibly locate two compounds which could give the same NMR spectra. In real life, such a possibility for two complex compounds that look so different is very unlikely. However, the assertion that this could be so is a testable and falsifiable hypothesis and therefore a good one.
In the present paper, the Italian group finally tackles the problem using a set of high-level calculated NMR spectra that include H1 chemical shifts, coupling constants, and even COSY plots at the DFT level. The answers are unambiguous and clear; Porco and Rychnovsky's hexacyclinol gives much smaller errors between measured and calculated parameters compared to La Clair's "hexacyclinol". At the same time, there is some striking similarity between many of the NMR parameters. In the end though, a competent organic chemist would be able to tell that the spectra belong to different structures. As the authors put it rather clearly,
The structure of hexacyclinol is confirmed to be (2). Furthermore, if (1) had been synthesized or was formed from an unforeseen reaction, its NMR spectra are sufficiently different from those of (2) as to guarantee their distinction.Short of a miracle that the famed Bionic Brothers could spring now, I don't see what Dr. La Clair can do to validate his original proposal and synthesis. This should also again be a question for Angewandte Chemie who published the paper; I am sure all of us are curious to know what happened there.
I have talked on this blog several times before (see below) about computationally calculated NMR parameters coming of age, and this paper should reinforce their tremendous power in resolving confusion between organic structures. H1 chemical shifts can now be predicted to within a remarkable 0.1 ppm accuracy. Hopefully these studies should now encourage the widespread use of the relevant tools in organic chemistry.
Previous posts on hexacyclinol and computational prediction of NMR data: here, here, here, here and here
Update: Also discussed at In The Pipeline and The Chemistry Blog. As mentioned in the comments, I too find it remarkable that Angew Chem has not published some kind of explanatory note by now, after all the blog and news publicity that the issue got.
Reference:
Giacomo Saielli, Alessandro Bagno (2009). Can Two Molecules Have the Same NMR Spectrum? Hexacyclinol Revisited Organic Letters DOI: 10.1021/ol900164a
Met/VEGFR/FGFR inhibitors by VS
This one comes from a NCI group. Starting with a database of 3.5 million compounds, 175 prospective candidates were finally selected for inhibition of Met kinase by virtual screening based on filtering by size, log P, polarity, h-bond donors and acceptors etc. The 175 compounds were docked by GOLD and 70 were selected on the basis of force-field calculated protein-ligand interaction energies (always a risky endeavor, but for a similar series, errors may cancel). For paring down the compound set, an empirical pharmacophore based on the usual kinase interactions (eg. h-bonding to hinge residues and h-bonding to a crucial Tyr to keep the kinase locked in the inactive conformation) was used.
The 70 compounds bought from vendors were assayed in cell-free Met assays as well as HGF (hepatocyte growth factor) induced Met activation. 3 compounds were chosen with modest Met inhibition IC50 values of 0.6 and 40 µM. The IC50s for the intact cells were 30, 50 and 30 µM. In spite of this less than stellar inhibition performance, the three were tested for the inhibition of other kinases and found to inhibit VEGFR and FGFR to similar extents. Since the single-kinase inhibition paradigm seems to be called into question these days, one might as well diversify. The different inhibition values were rationalized on the basis of hydrogen bonding and other interactions (or the lack thereof) by docking. Wisely, docking and docking scores were not used for judging binding affinity, just the orientations of the compounds in the active sites.
The flavone-like looks of the compounds make me quite suspicious about PK and Tox. Only time will tell. But Met is emerging as a valuable target.
Reference:
Megan L. Peach, Nelly Tan, Sarah J. Choyke, Alessio Giubellino, Gagani Athauda, Terrence R. Burke, Jr., Marc C. Nicklaus and Donald P. Bottaro (2009)
Directed Discovery of Agents Targeting the Met Tyrosine Kinase Domain by Virtual Screening
J. Med. Chem ASAP
Year of Charles
Two hundred years ago this day, Charles Darwin was born. The vision of life that he created and expounded on transformed humanity's perception of its place in the universe. After Copernicus's great heliocentric discovery, it was Darwin's exposition of evolution and natural selection that usurped human beings from their favoured place at the center of the universe. But far from trivializing them, it taught them about the vastness and value of life, underscored the great web of interactions that they are a part of, and reinforced their place as both actor and spectator in the grand ball game of the cosmos. Not only as a guiding scientific principle but as an all-encompassing element of understanding our place in the world, evolution through natural selection has become the dominant idea of our time. As the eminent biologist Theodosius Dobzhansky put it quite simply, nothing in biology makes sense except in the light of evolution. Evolution is a fact. Natural selection is a theory that is now as good as a fact. Both evolution and natural selection happen. And both of them owe their exalted place in our consciousness to a quiet, gentle and brilliant Englishman.
Today, it is gratifying and redeeming to know how right Darwin was and how much his theory has been built upon, and extremely painful to know how those who wield religious power threaten to undermine the value of his and others' careful and patient discoveries. Especially in the United States, evolution has become a bizarre battleground of extreme opinions and mudslinging, a development that seems to be in step with the tradition of coloring any and every issue with a political hue. In this country, it seems today that you can hardly utter an opinion without attaching a label to it. You cannot simply have an opinion or take a position; it has to be Republican, Democrat, Libertarian, Neo-Conservative, Socialist or Atheist. if none of these, it has to be Centrist then.
When it comes to evolution, attaching the label of "Darwinism" has completely obscured the importance and power of the theory of natural selection. On one hand, those who defend the label sometimes make it sound as if Darwin was the beginning and end of everything to do with evolution. On the other hand, those who oppose the label make it sound like all of us who "believe" in evolution and natural selection have formed a cult and get together every weekend to worship some Darwin idol.
Unfortunately both these positions and more obfuscate the life and times of the man himself, a simple, gentle and brilliant soul who was born two hundred years ago, who painfully struggled with reconciling his view of the world with religious ones and who thought it right to cast his religious views aside in the end for the simple reason that his findings agreed with the evidence while the others did not. Darwin Day should be a chance to celebrate the life of this remarkable individual, free from the burdens of religion and political context that his theory is embroiled in today. Because so much has been said and written about Darwin already, this will be more of a personal and selective exposition. Since I am a lover of both Darwin and books, I will tell my short story of Darwin as I discovered him through books.
When you read about his life for the first time, Charles Darwin does not evoke the label of "genius", and this superficial incongruence continues to beguile and amaze. His famous later photographs show a bearded face with deeply set eyes. His look is gloomy and boring and is not one which elicits the image of a sparkling world-changing intellect and incendiary revolutionary taking on an establishment steeped in dogma. Darwin was not a prodigy by the standards of William Hamilton or Lord Kelvin, nor did he particularly excel in school and college. A Cambridge man who studied religion, Darwin had one overriding quality; curiosity about the natural world. He consummately nurtured this quality in field trips and excursions; as one famous story goes, Darwin once held two beetles in two hands and popped one of them in his mouth so that he could have one hand free for catching a third very attractive one which he had just noticed. He indulged in these interests much to the chagrin of his father who once said that he would not amount to anything and that he would be a disgrace to his family.
As is well-known, Darwin's story really begins with his voyage of the Beagle when he accepted a position on a ship whose melancholic, manic-depressive captain Robert Fitzroy wanted an educated, cultured man to keep him company on a long and dangerous voyage that circumnavigated the world. For Darwin, this was a golden chance to observe and document the world's flora and fauna. One of the best illustrated expositions of Darwin's voyage is in Alan Moorhead's "The Voyage of the Beagle" which is beautifully illustrated with original drawings of the wondrous plants, animals and geological formations that Darwin saw on the voyage. Darwin's own account of the voyage is characteristically detailed and modest and depicts a man enthralled by the beauty of the natural world around him. By the time he set off on his historic journey, young Charles had already been inspired by his teacher Charles Lyell's book on geology that talked about geological changes over time. As is also rather well-known, evolutionary ideas had been in the air for quite some time by then, and Darwin certainly was not the first to note the rather simple fact that organisms seem to have changed over time, a view that nonetheless and naturally flew in the face of religious dogma. Most importantly, Darwin was well-aware of Thomas Malthus's famous argument about the proliferation of species exceeding the resources available to them, an idea whose logical extension would be to conjecture a kind of competition between species and individuals for finite resources. The "struggle for survival", taught today in school textbooks, a phrase that became much maligned later, nonetheless would have been obvious to a man as intelligent and perceptive as Darwin when he set off on his voyage.
Biology, unlike mathematics or physics, is a science more akin to astronomy that relies on extensive tabulation and observation. Unlike a theoretical physicist, a biologist would be hard-pressed to divine truths about the world by armchair speculation. Thus, painstakingly collecting and classifying natural flora and fauna and making sense of its similarities and differences is a sine qua non of the biological sciences. Fortunately, Darwin was the right man in the right place; endowed with a naturally curious mind with an excellent memory for assimilation and integration, he was also unique and fortunate to embark on a worldwide voyage that would enable him to put his outstanding faculties to optimum use. Everywhere he went, he recorded meticulous details of geology, biology, anthropology and culture. His observation of earthquakes and rock formations in South America and his finding of fossils of giant mammals lend credence to his beliefs about organisms being born and getting extinguished by sometimes violent physical and planetary change. His observation of the Pacific and Atlantic islanders and their peculiar customs underscored the diversity of human life along with other life in his mind. But perhaps his best known and most important stop came after several months of traveling, when the ship left Ecuador to dock at the Galapagos Islands.
Again, much has been written about the Galapagos Islands and Darwin's Finches. The truth is more subtle, sometimes simpler and more interesting than what it is made out to be. Darwin's had mistook his famous finches for other species of birds. It was only after coming back that his friend, the ornithologist John Gould, helped him to identify their correct lineage. But finches or not, the birds and the islands provided Darwin with a unique opportunity to study what we now know as natural selection. The islands were separated from each other by relatively small distances and yet differed significantly in their geography and flora and fauna. On each island, Darwin observed similar plants and animals that were yet distinct from each other. As in other places, he also observed that species seemed to be adapted to their environment. Geographic isolation and speciation were prominent on those hot, sweaty and incredibly diverse land masses.
After five years of exhaustive documentation and sailing, Darwin finally returned home for good, much changed both in physical appearance and belief. His following life has been the subject of much psychological speculation since he settled down with his cousin Emma and never ever left the British Isles again. He also seemed to have been stricken with what today is noted by many authors as a kind of psychosomatic illness because of which he was constantly ill with abdominal and other kinds of pains. After living in London for some time, Darwin retired to Down's House in Kent where he peacefully lived the rest of his life with a kind and loving wife, playing with his children, taking walks along the path at the back of his house named the "Sandwalk", corresponding with intellectuals around the world and constantly interrupting his research with salutary visits to spas and resorts for "natural" treatments that were sometimes of dubious value.
But peaceful as his life was, psychologically Charles Darwin was fomenting a maelstrom of revolution that was to have earth-shaking implications. Another fact that is frequently emphasized is his hesitation to not publish his ideas for another twenty five years in the form of the famous "The Origin of Species". Darwin was planning to write it for a while, but was finally jolted into writing it when he received a letter from an obscure young naturalist named Alfred Russell Wallace who was living a hard life of science and natural history exploration in Indonesia. Wallace had read some of Mr. Darwin's papers and manuscripts and had been struck by the similarity of his ideas to his own. Would Mr. Darwin comment on them? Darwin finally realized that he had to act to prevent getting scooped but characteristically credited Wallace in his published work.
In my mind however, Darwin's procrastination and its story sounds much simpler than the mystique and psychological speculation that sometimes envelops it. As we noted earlier, Darwin was a highly trained biologist and scientist of the first caliber. He knew that he would have to exhaustively document and classify the windfall of creatures, plant and rock specimens that he had collected on his voyage. Apart from thinking and writing about his Beagle collections, Darwin also maintained an astonishingly comprehensive and detailed research program on marine invertebrates and barnacles. More tellingly, he did experiments to find out if seeds are viable even when dispersed over long distances over salt-water. He visited gardens and zoos, and quizzed pigeon breeders about their profession. Much of this was in preparation for the grand act that was to follow. In case of the barnacles and marine creatures, Darwin's research was second to none. He published several extremely detailed books on the minutiae of these organisms; some of these had titles which would have put anyone to sleep. And yet the level of details in them reflects the extraordinary patience, power of observation and meticulous hard work that characterized the man, characteristics crucial for developing the theory of natural selection. Darwin was also very fortunate to have had several friends and colleagues who were experts in areas that he was not, who helped him classify and name all the material. Foremost among his correspondents were Charles Lyell and Joseph Hooker to whom he confided not just his scientific questions but also his emerging convictions about the interconnections and implications that were emerging from his research and writing. Also as noted above, John Gould accomplished the crucial task of reminding Darwin that his Galapagos birds were finches. With help from these collaborators and his own studies and thoughts on his observations, thoughts that filled literally dozens of rough drafts, scribblings and private diaries, Darwin finally began to glimpse the formation of a revolutionary chain of thought in his mind.
But Darwin did not rush forth to announce his ideas to the world, again for reasons that are obvious; Victorian England was a hotbed of controversy between science and religion, with many distinguished and famous scientists there and in other countries not just fervently believing in God, but writing elegant tomes that sought a supernatural explanation for the astounding diversity of life around us. Cambridge was filled with intellectuals who sought a rational framework for God's intervention. Darwin would have been quite aware of these controversies. Even though Darwin's grandfather himself had once propounded an evolutionary view, Darwin was finely attuned to the sensitive religious and social debate around him. Not only did he not want to upset this delicate intellectual and spiritual balance and get labeled as a crackpot, but he himself had not started his voyage as a complete non-believer. One can imagine the torment that he must have faced in those early days, when the evidence pointed to facts that flew in the face of deeply-held or familiar religious beliefs. One of the factors that dispossessed Darwin of his religious beliefs was the stark contradiction between the observation of a cruel and ruthless race for survival that he had often witnessed first hand, and the image of an all-knowing and benign God who kindly reigned over his creations. As the evidence grew to suggest a relationships between species and their evolution by the forces of natural selection that preserved beneficial characteristics, Darwin could no longer sustain two diametrically opposite viewpoints in his mind.
Opponents of evolution who want to battle the paradigm not from a scientific viewpoint (because they can't) but from a political one frequently raise a smokescreen and proclaim that evolution itself is too complex to be understood. The charlatans who propagate intelligent design further attest to the biochemical complexity of life and then simply give up and say that only an omniscient God (admittedly more complex than the systems whose complexity they are questioning) could have created such intricate beauty. The concept of a struggle for survival has also been hijacked by these armies of God who proclaim that it is this philosophy that would make evolution responsible for genocide, fascism and the worst excesses of humanity. This is a deeply hurtful insult to natural selection and evolution as only the most dogmatic believers can deliver. Stripped down to its essentials, the "theory" of evolution can be understood by any school child.
1. Organisms and species are ruthlessly engaged in a constant struggle for survival in which they compete for finite resources in a changing environment.
2. In this struggle, those individuals who are more adapted to the environment, no matter how slightly, win over other less adapted individuals and produce more offspring.
3. Since the slight adaptations are passed down to the offspring, the offspring are guaranteed to preserve these features and therefore are in a position to survive and multiply more fruitfully.
4. Such constant advantageous adaptive changes gradually build up and, aided by geological and geographical factors, lead to the emergence of new species
In my mind, the beauty of evolution and natural selection is two-fold; firstly, as Darwin emphasized, the slightest adaptation leads to a reproductive advantage. Such slight adaptations are often subtle and therefore sometimes can sow confusion regarding their existence. But the confusion should be ameliorated by the second even more striking fact; that once a slight adaptation exists, it is guaranteed to be passed on to the offspring. As Gregor Mendel hammered the mechanism for natural selection in place a few years after Darwin with his discovery of genetic inheritance, it became clear that not every one of the offspring may acquire the adaptation. The exact pattern may be complex. But even if some of the offspring acquire it, the adaptation is then guaranteed to confer reproductive fitness and will be passed on. This fact should demolish a belief that even serious students of evolution and certainly laymen have in the beginning; that there is something very uncertain about evolution, that it depends too much on "chance". The key to circumvent these misgivings is to realise the above fact, that while adaptations (later attributed to mutations) may arise by chance, once they arise, their proliferation into future generations is virtually certain. Natural selection will ensure it. That in my mind is perhaps Darwin's greatest achievement; he finally found a mechanism for evolution that guarantees its existence and progress. As for the struggle for survival, it certainly does not mean that it results in non-cooperation and purging of other individuals. As examples in the living world now document more than convincingly, the best reproductive fitness can indeed come about through altruistic leanings and cooperative behaviour.
Every one of these factors and facts was detailed and explained by Darwin in "The Origin of Species", one of the very few original works of science which remain accessible to the layman and which contained truths that have not needed to be modified in their basic essence even after a hundred and fifty years. It was readable even when I picked it up as a callow young college student. No one who approaches it with an open mind can fail to be taken with its simplicity, elegance and beauty. Its essential arguments are as true today as they were then. One of the most extraordinary things about Darwin and something that continues to stupefy is how right the man was even when he lacked almost all the modern tools that have since reinforced basic evolutionary ideas. As one of Darwin's intellectual descendants, the great biologist E O Wilson says, it is frustrating for a modern biologist to discover an evolutionary idea through his work, and then go back a hundred and fifty years and discover that the great man had hinted at it in his book.
And yet, as Darwin himself would have acknowledged, there is much in the book that needed to be modified, there was much that did not explain. Darwin had no inkling of genes and molecular biology. The exact mechanism of passing on adapted characteristics was unknown. Major fossils of primates and humanoid ancestors had yet to be discovered. Quite importantly, random genetic drift which is completely different from natural selection was later discovered as another process operating in evolution. The development of viral and bacterial resistance in causing diseases like AIDS finally brought evolution to the discomfort of the masses. It was only through the work of several evolutionary biologists and geneticists that Darwin finally became seamless integrated with the understanding of life in the middle twentieth century. But in the absence of all these developments, it is perhaps even more remarkable how many of Darwin's ideas still ring true.
There is another factor that shines through in "The Origin"; Darwin's remarkable modesty. One would have to search very hard in history to find a scientist who was both as great and as modest. Newton may yet be the greatest scientist in history, but he was nothing if not a petty, bitter and difficult man. Darwin in contrast was a symbol of kindly disposition. He doted on his children and told them stories. He loved and respected his wife even though their religious views gradually grew more distanced. His written correspondence with her was voluminous and fond. His correspondence with his collaborators, even those who disagreed, was cordial and decent. Never one for contentious public debates, he let his "bulldog" Thomas Henry Huxley fight his battles; one of them with Bishop Samuel Wilberforce ended in a famous showdown when the Bishop inquired whether it was through his father or mother that Huxley had descended from an ape, and Huxley countered that he would rather descend from an ape than from the Bishop. Darwin stayed away from these delicious confrontations; as far as he was concerned, his magisterial work was done and he had no need for public glory. To the end of his life, this kind and gentle man remained a wellspring of modest and unassuming wonder. His sympathetic, humane and sweet personality continues to delight, amaze and inspire reverence to this day.
In the later stages of his life, Darwin became what he himself labeled as an agnostic but what we today would probably call an atheist. His research into the progression of life and the ruthless struggle that it engenders made it impossible for him to justify a belief in a paternal and loving deity. He was also disillusioned by popular conceptions of hell as a place where non-believers go; Darwin's father was a non-believer and yet a good doctor who treated and helped hundreds of human beings. Darwin simply could not accept that a man as kind as his father would go to hell simply for not believing in a version of morality, creation and life trotted out in a holy book. Probably the last straw that convinced Darwin of the absurdity of blind faith was the untimely death of his young daughter Annie who was his favourite among all the children. According to some accounts, after this happened, Darwin stopped even his cursory Sunday trips to church and was satisfied to take a walk around it while not at all minding his wife and children's desire to worship inside. The second fact is also in tune with Darwin's kind disposition; he admittedly had no problem reconciling the personal beliefs of other people with his conviction about their falsity. Darwin's tolerance of people's personal faith and his unwillingness to let his own work interfere in his personal life and friendships is instructive; to the end he supported his local parish and was close friends with a cleric, the Reverend John Innes. Darwin's example should keep reminding us that it is actually possible to sustain close human bonds while having radically different beliefs, even when one of these is distinctly true while the other one is fantasy. Nurturing these close bonds with radical scientific ideas that would change the world for ever, Charles Darwin died on April 19, 1882, a content and intellectually satisfied man.
To follow, nourish and sustain his legacy is our responsibility. In the end, evolution and Darwin are not only about scientific discovery and practical tools arising from them, but about a quest to understand who we are. Religions try to do this too, but they seem to satisfied with explanations for which there is no palpable evidence and which seem to be often contradictory and divisive. It is far better to imbibe ourselves with explanations that come from ceaseless exploration and constant struggle; the very means that constitute these explorations are then much more alluring and quietly fulfilling than any number of divergent fantasies that can only promise false comfort. And these means promise us a far more humbling and yet grand picture of our place in this world. Especially in today's age when the forces of unreason threaten to undermine the importance of all the beautiful simplicity in the fabric of life that Darwin and his descendants have unearthed, we owe it to Charles Darwin to continue to be amazed at the delightful wonder of the cosmos and life. We owe it to the countless shapes and forms of life around us with whom we form a profoundly deep and unspoken connection. And we owe it to each other and our children and grandchildren to keep rationality, constructive skepticism, freedom and questioning alive.
LITERATURE ON DARWIN:
I don't often write about Darwin and evolution here for a simple reason; there are scores of truly excellent authors and now bloggers who pen eloquent thoughts about these subjects. There is enough literature on Darwin and evolution to fill up an encyclopedia of its own. His original work as stated above is still very readable. Every aspect of his life and work; the scientific, the psychological, the social, the political and the personal has been exhaustively analyzed. I have certainly not sampled more than a fraction of this wealth of knowledge, but based on my long interest in Darwin and selected readings, I can recommend the following.
For what it's worth, if you want to have the best overview of Darwin's life after he came home from his voyage on the Beagle, I think nothing beats the elegance of language and wit of David Quammen's "The Reluctant Mr. Darwin". Quammen has exhaustively researched Darwin's post-Beagle life and work, and no one I have come across tells the story with such articulate enthusiasm, fondness and attention to detail in a modest sized book.
Janet Browne's magisterial biography of Darwin is definitely worth a look if you want to get all the details of his life. Browne pays more attention to the man than the science, but her work is considered the authoritative work, and there are nuggets of eloquence in it.
As a student in high school, I was inspired by Alan Moorehead's "The Voyage of the Beagle" noted above which combines an account of Darwin's life and voyage with beautiful and full page illustrations.
Geting to evolution now, there's an even bigger plethora of writings. Several books have captured my attention in the last many years. I don't need to extol the great value of any (and indeed, all) of Richard Dawkins' books. If you ask me which ones I like best, I would suggest "The Selfish Gene", "The Extended Phenotype", "Climbing Mount Improbable" and "The Blind Watchmaker". For a journey into our ancestral history, Dawkins' strikingly illustrated "The Ancestor's Tale" is excellent. Speaking of ancestral history, a wonderful book published recently by Neil Shubin, "Our Inner Fish", charts a fascinating course that details how our body parts come from older body parts that were present in ancient organisms. Shubin talks for instance about how hernias are an evolutionary remnant. This is one of the best books around for understanding our evolutionary history. Another great general introduction to evolution is Carl Zimmer's "Evolution"
No biologist- not even Dawkins- has had the kind of enthralling command over the English language as Stephen Jay Gould. We lost a global treasure when Gould died at age sixty. His books are relatively difficult to read and for good reason. But with a little effort, they provide the most astonishing synthesis of biology, history, culture and linguistic exposition that you can ever come across. And all of them are meticulously researched. Out of all these, I personally would recommend "Wonderful Life" and "The Mismeasure of Man", and if you want to challenge yourself with a really difficult unedited original manuscript written just before he died, "The Hedgehog, the Fox and The Magister's Pox". In general, pick up any Gould book and you would have access to an extraordinary writer and mind. His collections of essays are also outstanding.
I don't want to really write about books which criticize creationism, because for me it's extremely painful to see how and why such a bizarre fallback to antiquated ideas keeps rearing its head in this country. But if you want to read one book about the controversy that rips apart intelligent design proponents' arguments, read Ken Miller's "Finding Darwin's God" which makes mincemeat out of the usual "arguments from complexity" trotted out by creationists which are actually "arguments from personal incredulity". He also has a new book which covers the 2005 Dover Trial. I have only browsed it but it seems to be equally good read. What makes Miller intriguing and puzzling is that he is also an ardent Christian.
There are others, but I will end with recommending a book published less than a month back which is getting great reviews and which I am currently reading- Jerry Coyne's "Why Evolution is True". The simple title says everything that is to be said about evolution.
Another entertaining exchange
You may remember that Manfred Christl who is emerging as a kind of vigilante of incorrect chemical structure determinations had debunked a previous claim and shown it to be a manifestation of a 100 year old reaction. There he goes again about the structure of some alleged cyclic allenes. But this time accompanied by a firm rebuttal; it's not often that you see the strong word "incorrect" in a scientific publication.
Are strained amides, where delocalization of the nitrogen electron lone pairs is not possible, still amides? Hell, yes!
References:
Manfred Christl, Bernd Engels (2009). Stable Five-Membered-Ring Allenes with Second-Row Elements Only: Not Allenes, But Zwitterions Angewandte Chemie International Edition, 48 (9), 1538-1539 DOI: 10.1002/anie.200803476
Vincent Lavallo, C. Adam Dyker, Bruno Donnadieu, Guy Bertrand (2009). Are Allenes with Zwitterionic Character Still Allenes? Of Course! Angewandte Chemie International Edition, 48 (9), 1540-1542 DOI: 10.1002/anie.200804909
Graham Farmelo's long-awaited Paul Dirac biography
...is now out. Tom Feilden holds forth on it
"Beauty is truth, truth beauty. That is all ye know on earth, and all ye need to know."I remember telling an introvert friend that Paul Dirac is the unlikeliest person I have heard of who had a happy family life with children. If Dirac could do this, any one of us could.
This sentiment, from John Keats "Ode on a Grecian Urn", is one that many physicists would share - which is ironic considering that Keats regarded science (and particularly physics) as a destructive force, unweaving the rainbow of God's creation.
And yet an appreciation of beauty is central to Paul Dirac's understanding of the material world. Often referred to as the British Einstein, Dirac was one of the greatest physicists of the twentieth century, linking relativity and quantum mechanics for the first time and predicting the existence of antimatter.
Who? That's Paul Dirac: who alongside Bohr, Heisenberg and Schrodinger opened up the field of quantum physics, and in 1933 became the youngest theoretician to win the Nobel prize at the age of 31.
Dear New York Times
You disappoint me
Dear Sir,
I was rather shocked to notice that in your "Notable Deaths of 2008" slide show that included 44 famous people from the arts, medicine, literature, television, politics, cinema, music and journalism, the name of the legendary physicist John Archibald Wheeler was missing. Dr. Wheeler who worked on the Manhattan Project died on April 13, 2008 and was one of the century's greatest scientists and a national treasure. During his long and remarkably productive life in which he worked with Albert Einstein and Niels Bohr, Dr. Wheeler played a key role in shaping American science, education and government policy. While it was heartening to see an obituary of him in the New York Times, I was quite disconcerted to see no mention of him in the Notable Deaths of 2008 Multimedia slide show list. While I understand that such an enumeration cannot be all-inclusive, Dr. Wheeler's stature as an American scientific icon should ensure the inclusion of his name in any short list of famous American people who died in 2008. I sincerely and strongly hope that this omission would be corrected.
Thanking you,
Sincerely,
Ashutosh S. Jogalekar
Atlanta, GA
Wheeler worked on the atomic and hydrogen bombs, served as an advisor to high-profile Presidential scientific committees, mentored brilliant scientists and leaders like Richard Feynman and Kip Thorne, resurrected and pioneered rather neglected relativity research in the 60s, coined the word "black hole", rendered invaluable teaching service at Princeton and Austin and propelled American physics into the first rank. If a list of notable American deaths of 2008 does not include his name, I don't know whose name it should.
When it comes to public exposition of achievement, it seems that popular media sources always give science short shrift in preference to other areas like art and cinema. The rift between the two cultures keeps growing. Science was undoubtedly one of the core foundations of The American Twentieth Century. Now it threatens to slip away from beneath the twenty-first. The country neglects it to its own perilous detriment. John Wheeler would have been unhappy.
Dear Sir,
I was rather shocked to notice that in your "Notable Deaths of 2008" slide show that included 44 famous people from the arts, medicine, literature, television, politics, cinema, music and journalism, the name of the legendary physicist John Archibald Wheeler was missing. Dr. Wheeler who worked on the Manhattan Project died on April 13, 2008 and was one of the century's greatest scientists and a national treasure. During his long and remarkably productive life in which he worked with Albert Einstein and Niels Bohr, Dr. Wheeler played a key role in shaping American science, education and government policy. While it was heartening to see an obituary of him in the New York Times, I was quite disconcerted to see no mention of him in the Notable Deaths of 2008 Multimedia slide show list. While I understand that such an enumeration cannot be all-inclusive, Dr. Wheeler's stature as an American scientific icon should ensure the inclusion of his name in any short list of famous American people who died in 2008. I sincerely and strongly hope that this omission would be corrected.
Thanking you,
Sincerely,
Ashutosh S. Jogalekar
Atlanta, GA
Wheeler worked on the atomic and hydrogen bombs, served as an advisor to high-profile Presidential scientific committees, mentored brilliant scientists and leaders like Richard Feynman and Kip Thorne, resurrected and pioneered rather neglected relativity research in the 60s, coined the word "black hole", rendered invaluable teaching service at Princeton and Austin and propelled American physics into the first rank. If a list of notable American deaths of 2008 does not include his name, I don't know whose name it should.
When it comes to public exposition of achievement, it seems that popular media sources always give science short shrift in preference to other areas like art and cinema. The rift between the two cultures keeps growing. Science was undoubtedly one of the core foundations of The American Twentieth Century. Now it threatens to slip away from beneath the twenty-first. The country neglects it to its own perilous detriment. John Wheeler would have been unhappy.
Samoquasine is perlolidine after all
Here is another nice example of the application of C13 chemical shifts calculated using quantum chemistry to solve a dispute concerning the structure of a natural product. This one is from Peter Wipf's group at Pittsburgh who use C13 shifts calculated at the B3LYP/6-31+G(2d,p) level to ascertain that an alkaloid named samoquasine is identical to another one named perlolidine.
Samoquasine was isolated in 2000. At the time the original authors thought that they had isolated a new alkaloid and gave it a new name. Then in 2002 they proclaimed that the "new" substance was actually the same as an earlier identified substance called perlolidine. Then along came some other chemists in 2003 who again said that in fact samoquasine is different from perlolidine. Time to put an end to the squabble!
To resolve the dispute, Wipf's group constructed 48 isomers that could correspond to all combinations of samoquasine/perlolidine. They calculated chemical shifts for all 48 isomers and found out that only the chemical shifts of one particular isomer (perlolidine!) showed the least deviation with measured C13 chemical shift for samoquasine/perlolidine. This indicated that the original authors' assertion, that samoquasine was identical to perlolidine was in fact correct. Not only were the latter authors wrong, but Wipf also castigates their melting point and their lack of measurement of UV spectra that could have helped settle the dispute back then. In short, the previous study was not exactly a nice piece of experimental work. Ouch.
Carl Djerassi once said that the great value of computers in structure determination is to generate several straw men and then identify which ones are in fact straw men. This study serves to drive that point home and again shows the value of computational prediction of NMR chemical shifts in organic chemistry. However, I also wonder how much the results would have changed had the authors used the MPW1PW91 functional which has been found to be optimum for such calculations. Also recall that this technique was demonstrated in a famous incident a few years ago.
Reference:
Cody Timmons, Peter Wipf (2008). Density Functional Theory Calculation of
C13 NMR Shifts of Diazaphenanthrene Alkaloids: Reinvestigation of the Structure of Samoquasine A
The Journal of Organic Chemistry, 73 (22), 9168-9170 DOI: 10.1021/jo801735e
Blogging will be slow
I am finishing up my graduate work and moving on to a postdoc up in the chilly northeast. Detailed location best undisclosed for now. Blogging will therefore be slow, although I hope to toss out some erudite nonsense about the graduate school experience soon.
A Drug Design Class Act: ∆S or ∆H?
One of the most important relations in all of chemistry is the free energy relation ∆G = ∆H - T∆S. Tuning the potency of a ligand binding to a protein involves a fine balance between optimizing both entropy and enthalpy. In his review on the role of these two variables, Johns Hopkins's Ernesto Freire makes a very interesting observation; that for a given series of progressively improved set of drugs binding to a given protein, it's the enthalpy that becomes more and more favourable while the entropy pretty much starts out being favourable. Thus, it's enthalpy optimization that's the harder part in drug design.
Freire illustrates his observation by looking at two sets of famous drugs- HIV protease inhibitors and cholesterol-lowering statins. For example if we look at the progression of the protease inhibitors over time starting from about 1995 when we had good but not highly-potent drugs to about 2006 when we had greatly improved drugs, we essentially find the striking fact that while ∆S for drug binding was favourable to begin with in 1995, it's really a great improvement in ∆H that has made the drugs more potent through the years.
Thus Freire concludes that it's improving enthalpy of binding and not entropy that's the hard part in improving potency. The argument is fairly straightforward; favourable entropy depends on desolvation of the drug to get rid of water molecules, as well as displacement of water molecules from the active site by the drug. Both these events are more or less favourable for most drugs as most drugs are reasonably hydrophobic. Thus, high hydrophobicity can by itself confer favourable entropy. But tuning enthalpy is much harder for two reasons; first of all because as Freire notes, it is not possible yet to engineer hydrogen bonds to the tenths of angstroms needed for optimum energetic gain. Secondly, even a slight sub-optimal feature in hydrogen bonding can tip the scales because remember, the hydrogen bonds that the ligand forms with the protein are simply replacing strong hydrogen bonds that were previously formed with the surrounding water. Thus the new hydrogen bonds may not be as strong, and indeed may even be unfavourable with respect to the previous ones. From past discussions, recall that a mere 1.4 kcal/change in free energy from unfavourable hydrogen bonding can lead to a 10-fold loss in binding affinity ("Life is a 3 kcal/mol denizen"). Clearly one has to be careful while designing ligands to form hydrogen bonds. It's perhaps not surprising that hydrophobic effect-induced binding is the main stabilizing factor in both protein folding and ligand design; both man and nature apparently find it much easier to get binding affinity from hydrophobic interactions than polar ones.
These facts are borne out when we see the change in these two thermodynamic variables in the optimization of HIV protease inhibitors over time where, while ∆S is favourable to begin with, ∆H is actually positive and unfavourable at the beginning. Let's also not forget that potency is only the beginning for a ligand that needs to traverse many obstacles in order to be converted into a drug, including ADME-T optimization. Any one of these further modifications can modify the one or both of the thermodynamic variables and change the initially optimized potency.
However, since optimizing enthalpy is both more challenging and more important, Freire prescribes experimentally measuring the two variables as much as possible for every stage of the drug design process starting as early as possible. This can be best accomplished through Isothermal Titration Calorimetry (ITC) which can also shed light on enthalpy-entropy compensation, an important process in the binding of ligands.
Thermodynamic optimization is a tightrope walking act, a prelude to the ultimate juggling game that is drug design. Not only are you trying to balance several variables at once, but some of them are trying to actually pull you down. But simple strategies can quell at least some of these nefarious efforts and reward you with a fine ligand, if not drug.
Reference:
E Freire (2008). Do enthalpy and entropy distinguish first in class from best in class? Drug Discovery Today, 13 (19-20), 869-874 DOI: 10.1016/j.drudis.2008.07.005