Parallel worlds, parallel lives

"Parallel Worlds, Parallel Lives" is a documentary about Hugh Everett, the fascinating, brilliant and troubled physicist who conceived the idea of parallel universes, which have become a staple of science fiction ever since and are now being taken seriously even by serious scientists.

Everett received his PhD. from Princeton in the 1950s with John Wheeler. At the time the prevailing view of what happens when you observe a quantum system was the Copenhagen Interpretation which said that until you observe a quantum system it exists in a superposition of states; the wavefunction of such a system suddenly "collapses" when you observe it. This of course led to several dilemmas and paradoxes, the most famous one being Schrodinger's Cat. Several questions arose; when exactly does the wavefunction collapse? Who can collapse it? Everett bypassed the whole problem by assuming that quantum systems simply exist in many different states but in separate universes and you observe one of them. Thus the wavefunction does not collapse at all. This of course sounded fantastic, implying that at every moment, there is a copy of you for instance that splits into infinitely many copies in infinitely many universes. However, it did seem to provide a simple way out of Schrodinger's cat-type problems. The "many-worlds interpretation" of quantum mechanics has fascinated, troubled and interested scientists and laymen alike ever since.

Unfortunately, Bohr's "gospel" prevailed among physicists, and Bohr strongly disagreed with Everett in a meeting that Wheeler had set up between them. Disappointed and with a family history of depression, Everett left academia for good. He spent the rest of his life doing top-secret work for the government, coming up with algorithms and computer programs for modeling nuclear war. He apparently was very influential in suggesting nuclear weapons policy which the government adopted and several of his reports are still highly classified. One of the concepts he pioneered was the Lagrange multipliers method, a key tool in solving differential equations with constraints in diverse disciplines. He died suddenly of a heart attack in the 1970s. Everett had a drinking problem and a tragic family life. He was very distant from his children. His son who is the main subject in the documentary says that the only time he touched his father physically was after he died and the dead body had to be moved. Everett's daughter committed suicide, writing a bizarre suicide note saying that she was going to meet her father in a parallel universe.

The documentary is a NOVA documentary on PBS. It's about Everett's son, the musician Mark Everett (who seems to be quite successful with his band "The Eels") who sets out on a journey to Princeton, the Pentagon, Austin, Cambridge etc. to find out more about his father and speaks to such people as Charles Misner and David Deutsch. On the way he learns some quantum mechanics and gets to know his father much better. In the end he feels much closer to his father and seems to have finally received closure. It was rather touching to be honest and there is a sense of satisfaction in his son finally seeming to be at peace.

Note: A rather expensive biography of Everett has just come out. A cheaper, free version is a short Scientific American piece on him.

The origin of life cannot escape basic organic chemistry

One of the key challenges facing any theories of the molecular origins of life concerns the synthesis, stability polymerization and self-assembly of early life's molecular components. If you cannot explain the chemical origin of these components, you cannot really explain the origin of life. In case of life as we know it, this boils down to explaining the origin of the building blocks of living organisms, namely nucleotides and amino acids.

The simplest principles and quirks of chemistry could have had an influence on how life could have evolved. A neat paper in ACS Chemical Biology offers a potential explanation based on basic organic chemistry for why a certain class of phosphorylated nucleotides formed in preference to others, even though 'conventional' organic chemistry would dictate the opposite.

An anhydroarabinonucleoside has been postulated as an important potential precursor to further nucleotide synthesis. A key step is the phosphorylation of this nucleoside to yield an activated cyclic nucleoside phosphate. Having an activated molecule makes all the difference since activation primes the molecule to be attacked by further nucleophiles, thus triggering polymerization and growth.

However, the phosphorylation of the arabinose nucleoside raises a fundamental question (hopefully) familiar to sophomore organic chemistry students. Why does phosphorylation take place preferentially on the secondary 3'-OH while sterically, as every student of organic chemistry knows, it should be preferred much more on the primary 5'-OH?

To tackle this question, the authors get a crystal structure of the nucleoside in question. This x-ray structure shows an unusually short distance between the 2'-OH oxygen and the C2 carbon (2.7 A, a).


Energy optimization using quantum chemical techniques surprisingly does not get rid of the short distance. Because of this proximity, the 2'-OH can undergo an internal attack on this carbon to generate a reactive intermediate (1), whose ring can be opened in turn by a 3'-OH phosphate to form the activated phosphate product. Now, the 5'-OH also gets phosphorylated; it's just that it cannot attack the C3 carbon of the activated intermediate the way the 2'-OH can because it's not in proximity to this carbon the way the 2'-OH is.


The authors explain the short distance between the 2'-OH and the C3 carbon by postulating an interaction between the lone pair of the 2'-OH oxygen and the pi* orbital of the C2=N bond. This kind of interaction is quite familiar to organic chemists; it is invoked in the famous Burgi-Dunitz trajectory that enables nucleophilic attack on carbonyl carbons. Indeed, the authors perform a theoretical analysis that shows the angle of attack for the 2'-OH to be about a 100 degrees, close enough to the Burgi-Dunitz trajectory.

This is a classic case of there being two competing pathways in chemistry, one of which is preferred to the other because of a subsequent low-energy route that can be traversed. It's a common theme in chemistry and biochemistry and illustrates how otherwise counter-intuitive reactions can be accelerated by putting them at the top of the right energy cliffs. No matter how complex life may be, it still cannot get around the basic laws of organic chemistry. Score one for thermodynamics.

Choudhary, A., Kamer, K., Powner, M., Sutherland, J., & Raines, R. (2010). A Stereoelectronic Effect in Prebiotic Nucleotide Synthesis ACS Chemical Biology DOI: 10.1021/cb100093g

The aesthete

I had a great time visiting Santa Fe and Los Alamos over the weekend. At Los Alamos there is a nice little museum in Fuller Lodge, where the Manhattan Project scientists used to socialize on weekends. One of the amusing artifacts there is a set of two letters sent by Oppenheimer's secretary asking for a nail to be driven into the wall so that he could hang his hat. There is the first letter...and then there is the follow up.


It's remarkable that this intellectual aesthete did not have the practical drive to hammer a nail into the wall. One could not have imagined someone like Fermi or Feynman leaving the problem unattended for so long. In light of this it seems even more astonishing that a dyed-in-the-wool hands-off theoretician like Oppenheimer could not only direct a world-class group of Nobel Prize winning scientists and engineers to achieve the impossible in record time, but also keep the most practical details of an unimaginably vast project in his head. He even knew who was the best person in the country to manage the organic chemistry stockroom.

Physicist Victor Weisskopf of MIT said it well:

"He did not direct from the head office. He was intellectually and even physically present at each decisive step. He was present in the laboratory or in the seminar rooms, when a new effect was measured, when a new idea was conceived. It was not that he contributed so many ideas or suggestions; he did so sometimes, but his main influence came from something else. It was his continuous and intense presence, which produced a sense of direct participation in all of us; it created that unique atmosphere of enthusiasm and challenge that pervaded the place throughout its time"

Conformations of the stevastelins: A reassessment

Shameless self-promotion: my paper on the conformational analysis of cyclic antiviral peptides called stevastelins is now online on the Biopolymers site. Here's a brief overview.

The stevastelins are cyclic peptides that show promising antiviral activity against the vaccinia viral VHR phosphatase. These peptides are phosphorylated in vivo before they can inhibit their target protein. A group in Germany previously did a meticulous analysis of four diastereometric analogs of these peptides which included their synthesis, biological characterization and conformational analysis. However, the conformational analysis was done using force field conformational searches from a single force field, constrained by variables from the NMR data (coupling constant derived dihedral angles and NOESY derived distances). Using such a protocol, the group concluded that each of the four diastereomers exists as a single conformational family in solution.

The problem with constrained conformational searches (or constrained molecular dynamics for that matter) is that they constitute a rather self-fulfilling exercise, with the assumption that there is in fact a single conformation of the molecule under question. However, as I have often discussed on this blog, any molecule with a couple of rotatable bonds is going to exist as multiple conformers in solution, so an assumption of a single conformation would be fuzzy unless supported by more data. NMR by itself is of scant value in determining these conformations for thermodynamic and kinetic reasons. Plus, analyzing conformations using a single force field can be fraught with ambiguity, since every force field comes with its own set of parameters and convergence criteria. Especially trusting energies from force fields can be dangerous. In this case, the stevastelin peptides have 9 rotatable bonds each, so I thought it worthwhile to apply our previously developed and applied NAMFIS (NMR Analysis of Molecular Flexibility In Solution) methodology combining NMR variables with structures from extensive conformational searches to the enumeration of the conformational behavior of these interesting molecules.

The paper essentially describes the conformational variability obtained for each of the diastereomers. Many of the conformations are very similar to the previously postulated families, but some are quite different. There are also some striking observations that are corroborated; for instance, the use of a d-serine truly seems to 'lock' the peptides in a single conformation. Such a lock could be effected to counter the entropic penalty that a multiconformational ensemble of molecules might have to pay. The instructive general observation is that subtle changes in sterechemistry at one or two chiral centers can dramatically affect conformational behavior, a fact that continues to surprise and confound medicinal chemists. I also note that if the NMR data for the phosphorylated peptides were available, an interesting comparison of the conformational pool for the phosphorylated and unphosphorylated counterparts could be attempted. This would shed light on whether phosphorylation leads to less conformational variability or simply increases the proportion of a chosen subset of conformations of the peptides.

Comments, criticism and general feelings of chagrin are welcomed.

Jogalekar, A. (2010). Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs Biopolymers DOI: 10.1002/bip.21504