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The Origin of Chirality in the Molecules of Life
A Revision from Awareness to the Current Theories and Perspectives of this Unsolved Problem
By Albert Guijarro, Miguel Yus The Royal Society of Chemistry
Copyright © 2009 Albert Guijarro and Miguel Yus
All rights reserved.
ISBN: 978-1-84755-875-6
CHAPTER 1
Introduction and Historical Background
1.1 Introduction
Chirality, or handedness, in molecules related to living organisms has fascinated scientists ever since the phenomenon was first observed, and it remains a fundamental question still not fully explained. Of the two possible series of enantiomeric molecules, why did Nature choose the L-amino acids and D-sugars when creating the structures of life? Why not the other way round? Indeed, why not both, which is at first sight the most likely chemical outcome?
For some scientists this is an encrypted clue provided by Nature to unveil its origins. For others it is much less than that, merely a matter of chance. We will describe in this book the most relevant pieces of information gathered by scientists over the past 150 years concerning this issue. Along the way we will explore some of the basic principles of the laws of Nature, principles which govern all the processes in the Universe, some of them so profound that they approach the limits of scientific knowledge, and which have influenced the nature of the Universe since its origin.
1.2 The Contribution of Pasteur
We are indebted to Louis Pasteur for the first theory on the origins of biomolecular homochirality — in fact we owe not only the initial theory to him but also our awareness of the problem itself. Most chemists are familiar with Pasteur's work on the resolution of tartaric acid (later known as racemic acid) into its enantiomers, a procedure which established the foundations of molecular stereochemistry (Figure 1.1). The historic chain of events which led in the middle of the nineteenth century to the development of molecular stereochemistry had its origins in the observation of chirality in compounds obtained from living organisms. Correlation of their crystallographic properties with those found in mineral samples — mineralogy being the better developed field at the time — provided the necessary understanding for this.
1.2.1 Quartz
Quartz had an important role to play. At the beginning of the nineteenth century, in 1801, the crystallographer R. H. Haüy observed that the apparent hexagonal symmetry of quartz crystals was in fact reduced in most cases by the presence of small faces called hemihedral facets (hemihedral meaning that only half the faces required for complete symmetry were exhibited) at alternate corners of the crystal. The presence of these hemihedral facets has a profound effect on symmetry. It eliminates the centre and planes of symmetry of the basic holohedral (holohedral indicating that it has the highest symmetry) hexagonal crystal, and gives rise to two non-superimposable mirror image forms of quartz, both chiral and enantiomorphic, which can be recognized by their outward aspect (further details are given in Section 8.2, Chiral Crystals and Faces on Crystals). Around the same time, the discovery of optical activity — a necessary tool in the study of chirality on the molecular scale — was attributed to the mathematician-physician, F. Arago in the early nineteenth century (1811), and it is equally related to the mineral quartz, since this was the first material in which optical rotation was observed. Soon afterwards the physicist, J.-B. Biot, discovered that natural quartz existed in two forms which rotated the plane of polarization in opposite directions, and he also established a linear relationship between the magnitude of the angle of rotation and the thickness of the slice of quartz (1812). In addition, he introduced and refined the polarimeter as a scientific tool. The two forms of quartz which Biot found to rotate in opposite senses in his polarimeter were subsequently identified by J. W. F. Herschel (1822) as the two hemihedral forms.
1.2.2 Tartaric Acid and the Tartrates
The wave theory of light was gaining acceptance at the time. Defended among others by the physicist A. J. Fresnel, the theory of transverse waves led to the conclusion around 1824 that linearly polarized light might be considered to be the superimposition of left- and right-circular polarized light. From this, it followed that the optical rotation was the consequence of the different refractive index of the two beams when passing through a chiral medium. Biot noticed that the effect of optical rotation in the plane of polarized light was not specific to crystals but was also found with certain natural products in the liquid state, including turpentine, aqueous solutions of sugar or tartaric acid (in 1832), and even vapors of such substances where they were volatile.
Later in the century (1843) Biot gave an intriguing account of certain anomalous relationships between two isomeric substances of formula C4H6O6, the naturally occurring (+)-tartaric acid and the optically inactive paratartaric acid, in relation to the law of isomorphism, discovered earlier by the mineralogist, E. Mitscherlich. This brought Louis Pasteur on to the scene, around 1847–48. Mitscherlich had compared the crystal forms of the corresponding salts of the two acids and found that they differed in crystal morphology, those obtained from (+)-tartaric acid being hemihedral and those derived from paratartaric acid holohedral racemic crystals (using current terminology), except in one instance. This was the case of sodium ammonium tartrate and paratartrate, in which the crystals appeared identical, and these salts displayed hemihedral morphology in both cases.
Pasteur decided the latter case required further study. Witnessed by Biot, Pasteur worked with tartaric acid, which Biot had shown to be optically active, and with paratartaric acid, which was chemically identical but optically inactive, and prepared crystals of the corresponding sodium ammonium salts. He showed that although both salts were indeed hemihedral, in the (+)-tartrate the hemihedral facets were all facing in the same direction, whereas in the paratartrate there were equal amounts of crystals with hemihedral facets having either this orientation or the opposite, forming a conglomerate of enantiomorphous crystals (for the definition of a conglomerate, see Section 5.6, Amplification of Scalemic Compounds: Eutectic Mixtures).
Figure 1.2 illustrates two actual enantiomorphous crystals of sodium ammonium tartrate, similar to those obtained by Pasteur in his work with racemic acid. In Figure 1.3b drawings of the two enantiomorphic crystals are shown, taken from Pasteur's original notes. These crystals are enantiomorphous, since they are mirror images and are not superimposable. Pasteur performed the first enantiomeric resolution of the crystals using tweezers and a magnifying glass. At the time he was aware of the work of Herschel, who had reported more than 20 years previously that left-handed quartz crystals were levorotatory whereas the corresponding right-handed crystals were dextrorotatory, i.e. enantiomorphous quartz crystals rotated the plane of polarized light in opposite directions (Figure 1.3b, and Section 3.2, Chiral Crystals and Faces on Crystals).
1.3 The Nature of the Problem
Crystals have a highly orderly structure. It seemed reasonable that chiral solids such as quartz or tartrate salts should be optically active. Unlike quartz, which is insoluble, tartrates are very soluble in water and remain optically active in solution, as demonstrated earlier by Biot. Since liquid phases are not organized structures, chirality is therefore a property of the molecules themselves. One of the two enantiomorphous crystals of the racemate yielded (+)-tartaric acid after acid treatment, identical to the tartaric acid deposited by maturing wines. On the other hand, the optically inactive racemic acid, consisting of a mixture of equimolecular amounts of (+)- and non-natural (-)-tartaric acid, was obtained for example by synthesis (among other sources), and in common with chemical syntheses at the time this was a racemic synthesis.
It is at this point that the fundamental question has to be asked: why does Nature display a preference for one of these two apparently equivalent molecules? Moreover, why is there a preference of this kind with most organic molecules in living organisms? Pasteur proposed at that time the first theory of the origins of biomolecular homochirality: the existence of chiral, or as he described them, dissymmetric forces in Nature. He dedicated in vain the remainder of his career as a chemist to the search for such dissymmetric forces in Nature. Perhaps his frustration in this area of chemistry helped to divert his efforts towards other fields of science. Indeed, his studies in microbiology were to provide the foundations of pathology, a keystone of medicine itself. Throughout this book we will see that, while he was unable to find these chiral forces, and that he was certainly mistaken interpreting some physical aspects concerning their chirality, his concept of an underlying asymmetric tendency in Nature was essentially correct.
CHAPTER 2
Theories of the Origin of Biomolecular Homochirality
2.1 Introduction
Experimental observations accumulated over the years have provided evidence leading — either tightly or loosely — to the various theories of the origins of biomolecular homochirality. They form a jigsaw of which some pieces are missing — perhaps in the form of definitive evidence — but this has not prevented preliminary interpretations of this puzzle being offered. And there have been many. Investigators have proposed a variety of hypotheses, but evidence in favor of each of them is at best fragmentary. Until a deeper level of understanding of the problem is reached and one theory prevails, there is a need to classify the various theories which have been proposed, possibly using different perspectives.
The first question to be asked in such a classification is whether there was in fact a cause, a specific chiral bias which provoked the mirror-symmetry breaking observed with biomolecules. If the answer to this question is negative, we are dealing with theories based on chance mechanisms — chance in the sense of randomness — and the grounds for this will be explained in the section following. If the answer is positive, then there is a relationship between cause and effect. In this case the observed mirror-symmetry breaking is a consequence of an earlier chiral influence, even if this is on a minuscule scale. This is consistent with the philosophical proposition of determinism, and we shall discuss it in terms of deterministic mechanisms and theories. These, to which most of this book is devoted, given their prolific nature, can be further divided into local deterministic and universal deterministic. They are local deterministic if the initial chiral influence existed in a specific given location (local in space), or over a limited period of time (local in time), but averages zero over large enough areas of observation or long enough periods of time. On the other hand, they are described as universal deterministic if there is a permanent, inexorable chiral influence, regardless of its strength (Scheme 2.1), at the time the chiral selection occurred.
Whereas in the first group, those concerning chance theories, one or more appropriate mechanisms should explain the randomness of the outcome, the ultimate chiral sign actually observed in the biosphere is certainly untestable, i.e., homochirality has developed simply by chance. Conversely, deterministic theories can be subjected to experimental confirmation, since if there was in fact a chiral influence that imposed its influence this should in principle be reproducible. This classification is not without some degree of overlap. This is easily observed within the subgroup of deterministic theories, for example (a) local deterministic or regional — the synthesis of prebiotic molecules on a chiral crystal of (+)-quartz, and (b) universal deterministic mechanisms — the result of the weak force. Local mechanisms always rely on a chiral manifestation which has its enantiomeric counterpart elsewhere, for example on a (-)-quartz crystal, which occurs with the same probability as its enantiomers, according to the latest studies, or at some other time, such as small circularly polarization of light at dawn, of opposite sign to that at dusk. From this point of view, deterministic local also has an element of a chance mechanism, represented in Scheme 2.1.
Among other classifications, the so-called biotic vs abiotic theories regard the origin of life as the ruling criterion, which could have taken place either before the enantiodiscrimination step (biotic theories) or afterwards (abiotic theories). Biotic theories, which entail coexistence of dextro- and levo-organisms followed by the extinction of one of them, have lost their appeal for most scientists. It could be tempting to invoke the occurrence of some D-amino acids in primitive organisms as a remnant of a racemic life parallel to ours, a primeval enantiolife which could have originated with the beginnings of evolution. This does not seem to be the case. Although a few unnatural D-amino acids are found in bacterial cell walls and other secondary metabolites, these are synthesized from the L-form, which is the only form coded by bacterial DNA.
2.2 Chance Theories
At first sight, chance mechanisms are somewhat counterintuitive to chemists. This is in part because chance mechanisms rarely have a role in conventional chemistry due to the statistical behavior of the samples involved, which consist of a very large number of molecules, often approaching the scale of Avogadro's number. We are accustomed to reproducible experiments every time we run them. The opposite would be the macroscopic manifestation of a single microscopic stochastic event, which would give random results every time we ran it. The scenarios of spontaneous symmetry breaking can be included in this category (Chapter 6, Spontaneous Symmetry Breaking) and are mainly associated with physical phenomena. Chemical reactions of this type are very much less common, in fact they were purely theoretical until very recently, with the advent of Soai's reaction (Section 5.2.4, Asymmetric Autocatalytic Reactions).
2.2.1 Amplification of Tiny Stochastic Imbalances
In principle, the evolution of biological homochirality could be theoretically explained by a model in which a tiny imbalance of one enantiomer was exaggerated, or amplified, by autocatalytic reactions. A chemical reaction is autocatalytic if the reaction product is itself the catalyst for that reaction. This concept is discussed in Section 5.2 under the heading Autocatalysis, and is mechanistically related to the well-known Frank model. However, concerning the minute imbalance, this must by definition be merely stochastic in origin. To clarify this point, some features of the racemic state will be summarized.
2.2.1.1 The Racemic State
In general, chiral molecules are obtained in the racemic state when synthesized from achiral reagents, for example inorganic or small organic starting materials. Racemism is, however, an intrinsically macroscopic attribute. A statistical description of the racemic state down to the individual molecule is, however, of interest for a variety of reasons. In principle the racemic state can be described by a binomial distribution. In its broad definition binomial distribution gives the discrete probability distribution Pp](n, N) of obtaining exactly n successes out of N Bernoulli trials, where the result of each Bernoulli trial occurs with probability p (and therefore the opposite occurs with probability 1 – p), represented by Equation (2.1). This treatment is subject to the constraint of the strict independency of each Bernoulli trial in regard to what has happened before. Tossing a coin is a good analogy, where the result of each flip, either head or tail, is independent of the previous history of results and has a probability p = 1/2. Translated to our racemic synthesis, this implies that are dealing with an irreversible synthesis, where the reaction products (D-and L-molecules) do not have any effect on the previous synthetic steps. A drawing of the probability distribution for this racemic synthesis is shown in Figure 2.1. As expected, the mean value of this distribution is µ = Np = N/2, while the standard deviation is σ = [square root of (Np(1 - p))] = [square root of (N/2)], in agreement with the properties of the binomial distribution. If the enantiomeric molecules D and L are synthesized with exactly the same probability, i.e., p = 1/2, the binomial distribution gives the discrete probability distribution P (N/2, N) of having exactly N/2 molecules of one kind (e.g., of D-configuration) and N/2 of the other (disregarding for simplicity the case in which N is odd, the effect of which vanishes for N large, in which case there are two modes instead of one, symmetrically centered around N/2). This probability is expressed by Equation (2.2), where the combinatorial numbers have been calculated using the Stirling approximation, Equation (2.3).
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Excerpted from The Origin of Chirality in the Molecules of Life by Albert Guijarro, Miguel Yus. Copyright © 2009 Albert Guijarro and Miguel Yus. Excerpted by permission of The Royal Society of Chemistry.
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