Pre-Biotic Evolution: From Stellar to Molecular Evolution

Pre-Biotic Evolution:

I. From Stellar to Molecular Evolution

Joseph H. Guth*

​​

One Scientist’s Overview and Perspectives

Introduction

The principle intent of this collection of essays is to conceptualize and provide a stepwise, detailed and plausible path for the formative and evolutionary processes before and up through when “life”, per se, began on earth. It explores and synthesizes some of the most relevant recent experimental, technological and theoretical developments. This series of essays will attempt to provide a road map for the experimental probing of the specific events and mechanisms which produced the very first origins of living systems. An understanding of what the minimum requirements are for a collection of abiotically created molecules being able to become organized into a “living” protocell may now be at hand for scientific exploration, experimentation and verification. Should science one day finally produce a pre-biotic-to-biotic laboratory model system to simulate the origin of life forms on earth, it could offer real guidance to our efforts to understand our actual chemical and physical origins. More importantly, it could allow us to develop new and more plausible approaches in exploring the universe at large for extraterrestrial life and all of its possible definitions and variations. Its ultimate impact will be immeasurable on human history.

Outline of this essay series

The overall phenomenon known as life begins with and is inextricably connected to the nucleosynthesis of the major elements of the Periodic Table. The production of those elements occurred in various stellar and astrophysical processes. Past supernovae provide just one of many sources of our elemental atomic building blocks. As Cosmos astronomer Carl Sagan observed, “We are made of star stuff”. Without the availability of so many resultant and differing types of atoms with their various symmetries and geometries, bonding potentials, and electronic energy states, life as we know it could not even have begun. By extension, the subsequent molecules that inextricably formed and evolved from them, constituting the matter making up living systems on earth today, also could not exist.

The lens through which the earliest stages of the origin of life may be illuminated begins with the basic tenets of physical chemistry, combinatorial reaction chemistry, biochemistry, bioenergetics, membrane biophysics, chaos theory, complexity theory and evolutionary theory. The challenges that are ultimately addressed are as follows:

  • How could a complex, dynamically balanced and interactive system made up of so many parts ever have come into existence?

  • How could this extraordinarily unlikely “whole” originate from the piecemeal addition of each of its “parts”?

  • How could the inherently low probabilities for each of these presumed pre-biotic steps actually have led to an inexorably predictable outcome for the genesis of life?

  • Life is a dynamic and complex process. What are the exact events that caused forms of molecular evolution to change into forms of process evolution?

  • What is the physical nature of life’s “energy” and how was it generated in the first living cell?

  • With a multitude of different “molecules of life” finally generated, how could such a collection in a state of relative thermodynamic equilibrium ever become assembled into a dynamic, exergonic, energy-containing assembly that continued to take in various forms of energy and matter and build new biomass?

It is usually the complexities and unknown or uncertain workings of living systems that baffles the scientific reductionist trying to probe or analyze the beginnings of life. But that classical scientific mindset is exactly what needs to be overcome in order to embrace a process that had innumerable components, steps, stages, variations and possible outcomes. It is the complexity and non-linearity of the living process that imbues “life” to inanimate matter. Life does not greatly depend upon random, stochastic processes. In fact, it is commonly described in opposite terms as being thermodynamically of a negative entropic nature. Though molecular biology is useful in observing and describing the structure of the living cell, it is a misnomer in that it does not actually address the complex “living” state. It only looks at snippets of the bigger, overall picture and that is where we must be able to have a clear view and understanding. When looking for the origin of life, a firm definition and operational design of life is quite indispensable. But in this series of essays, the underlying, non-stochastic patterns of molecular behavior and dynamic linkages create the necessary chaotic complexity that is required to more accurately describe the living state. The complexity of the living cellular system must not be dissected back into its parts to understand it. It is the way those parts interact and work together that provides the whole being greater than the sum of its parts. Can one understand how the space shuttle could fly and carry out its missions from just its parts list?

Our scientifically-based genesis story begins with inanimate atoms and logically carries through to the biophysical formation of the first proto-cells. In this series of essays, we find some new and interesting pieces of the puzzle fit together naturally. These stages of molecular and early cellular evolution might rationally end at a waymark in this narrative after prokaryotic and the earliest eukaryotic cells made their appearances for the first time. The level of presentation is less rigorous and specific in order to facilitate understanding by a wider, enlightened scientific audience. As such, brief introductory comments about specialized theories will hopefully benefit the majority of readers while not trying the patience of those more specialized in this subject.

After bringing the universal collection of various kinds of atoms into existence, we also must find common ground to agree on certain basic assumptions. Such assumptions as all atoms of a given element, no matter where they occur in the universe, are indistinguishable in their makeup, chemical and physical behavior and characteristics. Another assumption is a corollary to that which implies that all atomic reactions between atoms of identical or differing elements behave the same anywhere in the universe when under the same environmental conditions. That leads to the next corollary that all specific molecules formed from such reactions will have the same identical properties no matter where they occur if under the same environmental conditions. And the last corollary is that all molecules with the same structure will behave indistinguishably from one another if under the same conditions anywhere in the universe. These fundamental assumptions allow us to accept spectroscopically-derived astronomical data and interpreting it as being mechanistically identical with comparable laboratory or locally-generated data. Such assumptions are commonly accepted in astrophysics, astrochemistry and astrobiology.

We follow a similar trail to that which others described in which the pattern for protein-based metabolism could have preceded the appearance and functioning of a nucleic acid-connected, information-containing, accurately-transmitted, highly specific (genetic) molecular replication scheme.1 We begin with describing a picture of nonmembrane-bounded molecular evolution preceding that first membrane-packaged “cell” formation (i.e., the proto-cell).

There will be a very prominent role for the development of permanently oscillating, self-propagating, oxidation-reduction chemistry that provides the first form of life energy storage and conversion that future living systems will be built upon. Such systems can involve purely inorganic reactions assisted by catalytic species or can be found in organic chemically-based systems which can range from relatively simple to highly complex. In modern biochemistry, such oscillatory behavior is found in both cell-free and intact subcellular biochemical pathway dynamics. It is also reflected by oscillatory behavior in various transmembrane fluxes of different biochemicals and bioenergetically-important compounds and membrane-based ion transport mechanisms as well. Such oxidation-reduction coupled oscillations will ultimately become packaged as one of many forms of protocells which then survive as dynamic, chemically-reactive entities. Those protocells then would have been able to merge with other different, chemically-dynamic, oscillating protocells containing differing supermolecular complexes that were carrying out different sets of chemical reaction sequences. This aspect will be focused on in more detail in the coming installments.

Think of this as a time when there were different subpopulations of protocells, each of which contained all of the main enzymatic protein complexes for different future metabolic pathways such as glycolysis, electron transport, tricarboxylic acid cycle, pentose shunt, etc. Each subpopulation may have arisen in a single body of water with a combinatorial collection of all kinds of supermolecular complexes incompletely mixed together or in different adjacent or nearby bodies of water. Each pond or lake contained a variety of molecular mixtures and with hot rocky surfaces nearby. In this chemically-evolving, catalytically active world, complexity drives this natural tendency for molecular structure and reactivity to always spontaneously increase. As the different mixtures’ complexities grow, even low probability outcomes become more likely. Such is the power of combinatorial chemical catalysis. As newer molecules form, some of them will possess other catalytic capabilities that lead to even more subpopulations of molecular species. That increasing complexity provides the driving force for the development of highly complex, integrated systems. That ever-increasing complexity can increase the likelihood of protocells and living systems eventually appearing. Once such more complex assemblages of molecules and structure appear, if the selection conditions are present, those more complex units become the dominant subpopulation if they have developed any survival or propagational benefit from their environment at that time.

Protocell fusions occurred countless times between differing types to eventually

result in complex, highly-structured protocells with multiply-integrated, dynamically-oscillating pathway activities. It is reasonable to expect that only pathways that could be in resonance with one another in terms of their input reactants and output products would be capable of long term

stability and homeostatic behavior.

It will be noted that the self-sustaining collection or set of chemically-reacting molecules (both substrates and catalysts) that possessed many of the later characteristics of biochemistry and biological life were likely to have been already generated abiotically and assembled well before the membrane packaging of those molecular reactions and their enzyme-like assemblies. Those chemical reactions began with simple available starting materials self-sorted out of a complex, abiotic mixture generated combinatorially. The chemical reaction sequences within those mixtures that also became self-amplifying by generating more of the same catalytic capabilities in the end products they formed would have become more abundant. Those would have become established sooner than those that could not.

One example of that self-amplification is the modern day Polymerase Chain Reaction (PCR) used to replicate small amounts of DNA in vitro for analysis. Another is the replication mode of PrPSC prion proteins which is thought to be devoid of any DNA-directed involvement. It is even possible to place the first virus-like precursors within such a milieu if enough of their needed molecular replication machinery and molecular building blocks were co-constituents within our pre-biotic combinatorial ponds. Those “proto-viruses” would become the first self-replication genes and genomes existing before the first complete genomes, chromosomes or independent living cells were formed. But in our early earth case, those products were initially amino acid-based polymers possessing the same types of catalytic activity that initially produced them. And what allowed this to happen with a high probability? It was that they were most likely organized as multiple step, integrated reaction sequences that operated in a controlled feedback loop-like fashion.2, 3, 4, 5

Molecular Simplicity to Complexity

A Stellar Beginning

Let us start at the beginning. Our story of the origins of life began with simple chemistry and its universal occurrences. Hydrogen, carbon, nitrogen, oxygen, sulfur, sodium, potassium, calcium, magnesium and phosphorus are found throughout the universe. Astronomically large clouds of these elements are found throughout the galaxy having been transmuted through a sequential nucleosynthetic process occurring from the life and death of stars and other high temperature, high energy sources. Depending on the temperatures present, differing nuclear reactions and states of matter can exist within them. At higher temperatures, those elements are found primarily as atomically individual, electrically ionized plasmas with unassociated, free-moving electrons. At lower temperatures the oppositely-charged particles can remain associated with one another, and form ionized as well as neutrally-charged atoms and molecules. During this cooling down, mixtures of plasmas containing nuclei of different elements will form heteroatomic chemical bonds. Simple gaseous molecules like hydrogen (H2), oxygen (O2), water, all carbon-based fullerenes and graphite, methane (CH4), ammonia (NH3), nitrogen (N2), carbon monoxide (CO), formaldehyde (CH2O) and similar compounds will have readily formed. Many of these have been identified in spectra of stars, nebulae and molecular clouds. Formation of larger molecules might not be favored in space-based clouds however. Larger molecules would likely have to await the less severe ionizing conditions of planetary surfaces.

Once these smaller molecules collect and concentrate on cooler planetary and sub-planetary bodies, various chemical reactions and physical processes can continue to lead to larger molecular structures under more molecularly stable conditions. The production of life’s complex mixture of starting chemical compounds could have formed in large quantities on post-Hadean period earth as well as many other places in the universe. Such is the inevitable driving tendency of synthetic dynamic combinatorial chemistry. When there are a few different kinds of atomic building blocks and sufficient energy available to break chemical bonds along with conditions that allow new bond reformations, small simple molecules becoming increasingly larger and more complex in structure. And as new kinds of chemical structures come into existence in our mixtures, new catalytic potential is introduced with them. New catalytic potential spurs even faster development of ever-expanding libraries (i. e., collections) of newer compounds which hadn’t previously existed. Complexity in our early chemical incubators will ultimately lead to collections of linked chemical catalysis. Linked reactions form the basic pattern and framework for modern cell-based metabolism. And in our case it comes together on a cooling earth a little less than 4.5 billion years ago. The physical incubator for abiogenesis became available on the still hot, asteroid-bombarded surface of earth.

The chemical compounds which collected there initially must have originated from a combination of meteorite/asteroid plus cometary deposition and higher-temperature chemical reactions. These latter are known to occur between very simple molecules composing the early earth surface deposits and atmosphere. Similar high energy-associated chemistry could have already been occurring extra-terrestrially within the Oort cloud surrounding the infant solar system. The solar wind and the ionizing electromagnetic radiation it emitted bathed such frozen water- and methane-rich icy bodies with high energy particles and chemical bond-ionizing photons. Low- to extremely high-energy protons, electrons, neutrons, and other elementary particles (which are commonly known as cosmic rays) catalyzed new element nucleosynthesis and chemical bond formations after they traveled in on the solar wind, as well as from deeper interstellar and intergalactic sources. Physical shock waves due to impacts and sound vibrations and deep earth zones under very high compressive forces and temperatures can induce unusual chemical reactions to occur (such as crystallization of elemental carbon to diamond). In addition to the previously-generated elements, new elements formed from these cosmic ray transmutations and subsequent radioactive decay. These collected within the populations of chemical compounds on each of the various proto-planetary bodies orbiting the young sun.

This early earth setting frames the period and some of the necessary steps, stages and events leading up to and into the formation of the first cells on pre-biotic earth. It must be a brief overview since there are publication limitations in time, space and reader attention span. Such limitations were not present during the original story. That original reality had the advantage of having all the time in the world to play out. It evolved over the time span from approximately 4.2 to 3.6 billion years ago. This pre-life reaction chemistry began almost immediately after the earth cooled sufficiently and limited amounts of liquid water became available.

Molecular Evolution Leading to Pre-Life Chemistry

During the pre-biotic period, simple molecules were produced through a variety of chemical and physical processes. Some were generated on early earth in manners already described.6, 7, 8, 9, 10, 11, 12 Hydrogen, the most abundant (reducing) element in the cosmos, will usually be part of the early gases that collected as atmospheres on cooling planetary bodies. The hydrogen-rich reducing atmosphere, composed of gases found throughout space as nebulae and molecular clouds in the galaxy, were generated from within supernovae. And as modern exo-planetary research has repeatedly shown, they could have been expected to be abundant around our youthful Sun.13, 14, 15 The simple atoms and molecules of the periodic table found throughout the cosmos could have not only been plentiful, they could have been gravitationally attracted to any sizable body in an infant solar system. They collected on our newborn planet as it slowly swept through them.

This reducing atmosphere was originally low in molecular oxygen content and oxidizing potential. That was first postulated by Oparin and Haldane in the 1920s. It could have coalesced and formed over the solid surface of primitive earth soon after it finished cooling and solidifying out of a previous supernova cloud full of lighter and heavier elements. Through high temperature processes such as volcanism, geothermal steam, simple pyrolysis, high energy impacts, electrical arc heating (lightning) and ionizing radiation, it is likely that brownish-black, tarry, keragen-rich ooze would have developed and continuously accumulated over large land-based areas. Such organic molecule building generally is not found in oxidizing conditions.1 Growing molecular sizes for the organic compounds being generated abiotically would have built up over a great amount of time on or within various heated rock, sand and clay surfaces scattered around the globe. This was an early period of not just fairly arid conditions, it could have also been predominantly water-poor, dehydrating conditions for early reactive carbon chemistry to become relatively facile.

Differences in the area-specific mineral and gaseous contents, volcanism, temperature, pH, sun light intensity and spectrum, and other chemically important conditions at these different locations imparted complex but important nuances by way of the Butterfly Effect to the variety of chemical reactions taking place from one oasis of pre-biotic chemical genesis to another. But liquid water would likely have been sparse at this earliest part of the Hadean Eon. Volcanically-heated steam could likely have been found in a widely distributed niches amidst the water-poor areas. The conclusions of Lazcano and Bada regarding Miller’s experiment only portrayed a watery womb for the development of surprisingly high concentrations of a few more simple structured, biochemically-important, starting compounds in that primitive soup.16 The genesis of even more molecular complexity would likely have been seeded in a water-poor, higher temperature environment that favored condensation polymer formation.17, 18, 19 Thus the original drier and higher temperature range starting molecular recipe created one large population of larger molecular weight polymers. Once lower temperatures became the norm, and after more water became available, the conditions changed sufficiently so that a much more diverse and now biochemically-meaningful population of chemical compounds was available. That population worked better in aqueous environments and began to produce the next generation of products ultimately needed for the life process to finally organize and become self-propagating. During that phase, only integrated and highly effective molecular subpopulations that could resist or overcome the slow rate of hydrolysis would win a place in this post-combinatorial chemical water-world.

As an example, the transition from the arid to aqueous world during earth’s early history would have involved water-requiring chemical reactions. Water would be both a supporting solvent and a reactant. Variations in the yields of various products might have depended upon the availability of super-heated steam above certain reaction temperatures. When such water-based chemistry occurs along side anhydrous heated surfaces, many interesting compounds could result.20 Such closely juxtaposed reaction sites, as are found in present day geothermal environments like Yellowstone National Park in the United States, could have also more quickly modified the plethora of molecular species that could combinatorially form. Reaction products from dehydration-driven conditions would easily transport into more aqueous conditions where water-requiring oxidation-reduction electrochemical reactions would have been incubating. And as changes in the latter pools led to newer compounds, those could have been recycled back to the hotter dehydration conditions building up larger molecular species that were more resistant to hydrolysis and yet possessing of newer and unique molecular reactivities and properties. The complexity of the resultant molecular mixtures becomes the most important determinant as to whether the right combination of molecular species form abiotically. Without a minimum number of necessary interactive molecules being present, a living process would not be possible. Which is what we view as the origin of life’s greatest challenge. It defines the highly improbable nature of the generation of living cells from non-living matter that make them up. But if that minimum threshold number of compounds does come into existence in our mixtures, then what are the chances for life to spontaneously follow?

Complexity at the Beginning

Dynamic combinatorial chemistry is a specialized synthetic technique that is now a sub-discipline of the chemical sciences and was first developed by Merrifield in the 1960s21 and later by others.22, 23, 24 It has since become highly popular and a powerful technique for finding specific “needle-in-the-haystack” molecular interactions and associations from highly complex and undefined mixtures. It is commonly found in synthetic chemistry and analytical chemistry applications. In most applications, combinatorial chemistry is based upon the principle that if one allows all manner of possible chemical reactions to proceed unhindered, unselected, and without limitations, a broad range of possible reactions will occur and reaction products will form. Within that complex mixture of perhaps millions of different, uncharacterized compounds there could, through random chance, be some very small numbers of specific interactions of important biochemical or pharmaceutical consequence. Once the library of all those resultant compounds becomes available, then very specific conditions, probes or selectors can be introduced to dissect out just a few compounds from the astronomically large number of possibilities. If successful combinations occur, those have the necessary molecular structure, affinities, and reactivity needed for the end purpose. In chemical laboratory applications, those rare compounds can be quickly identified, filtered and isolated using appropriate affinity-based selection techniques. But under primeval earth conditions, the selection for those rare combinations would be made through a process of self-selection. In our origin-of-life experiment under combinatorial conditions, only those molecules that can react in just the ways that current metabolic pathways operate would have been spontaneously self-selected for. It could include any ultimate subset of catalytically-active, catalytically-controllable, self-amplifying, and self-perpetuating collections of molecules that might become the most prevalent and thus most likely to ultimately become packaged into proto-cells that form later. That packaging process will be detailed in subsequent parts of this essay.

Comets carrying large amounts of water, rock, frozen gases, and dust also started becoming more plentiful during this early period in earth’s history. They subsequently added sufficient free liquid water as the earth further cooled to begin forming pools, ponds, lakes, seas and eventually-frozen polar caps. After that hydration phase passed some critical threshold, membrane-bound life forms would have had an environment they could call home.

The originally dehydration-based pre-biotic chemistry now began to dissolve and suspend a growing variety of small, medium and larger molecular weight precursory pre-biotic molecules. It is this limited collection of compounds we shall refer to as the “starter set”. Niches and pockets of dehydration-based chemistry continued to generate the earlier reaction products while the water-based chemistry began to form a newer collection of pre-cursor, pre-biotic molecules. This latter group in part contained water-derived oxygen atoms within their structure. That increased their inherent polarities, water solubilities and reaction chemistry potentialities. Such wide climatic fluctuations simply emulate what we can still find anywhere on earth. Even arid deserts can experience infrequent flooding rainfall and rain forests can die off from drought-provoking climate changes. Chemical complexity now becomes the new paradigm. Virtually every chemical reaction pathway found in current synthetic organic chemistry could be co-existing at some location under these early earth conditions.

Pockets of minerals containing more reactive elements and atomic species (such as inorganic carbon, iron, manganese, cobalt, phosphorus, silicon, selenium, arsenic, iodine, sulfur, or copper) would provide even greater richness of molecular diversity in their own niche-like locations. A long-standing question has been “Why are so many inorganic elements found in key metabolic sites within living cells? How did they evolve to be there?”

Such an early history of exotic chemical reactions might have led to conservation and parallel evolutionary paths for various metallo-organics (such as metallo-porphyrins), metallo-enzymes, thiol/disulfide-containing proteins and unusual biochemical pathways. Examples of the latter group are the selenium-based superoxide dismutase enzymes, the iron-sulfur containing P450-FeS and cytochrome complexes in mitochondria and inner cytoplasmic membrane systems, the hydrogen peroxide-hydroquinone defense mechanism of the bombardier beetle, and the hydrogen, methanogenic and carbon/nitrogen/sulfur-fixing pathways of the Archaea. The high G-C DNA base composition and thermal stability of proteins in thermophiles in this latter group of ancient microorganisms also provide present day examples of such likely long-term conserved lineages.

After dry-cooking for millions of years, new classes of carbon-based chemistry began becoming common in water-rich pockets. It is the aqueous environments that are typically referred to as the “primordial or primeval soup” by many authors. Most theories involving the origin of life speculate that first “life” began in such a liquid environment. But without the earlier abiotic conditions and chemistry previously occurring in the dehydration zones, the genesis of a complex mixture of higher molecular weight polymers might have been much slower and present a statistically less-likely outcome. In proteins, nucleic acids, and polysaccharides, the bonds forming the primary monomer linkages are virtually all formed through the net removal of a water molecule and subsequently are usually easily hydrolyzed through simple addition reaction with a water molecule. Phospholipids are similarly formable through condensation under dehydration conditions.

The higher temperature conditions the molecules are subjected to typically favor the forward reaction for the reversible hydration-dehydration type reaction. The larger molecular skeleton aids in favoring the formation of somewhat more stable bonds. Loss of water is a common biochemical reaction found in biochemically important molecules. And the formation of those is favored and preferentially induced under higher temperature-driven, anhydrous reaction conditions. Increased temperatures will increase the stretching and vibration modes in covalent bonds. As the mean bond lengths increase even slightly, the bond dissociation energy is reduced and the bonds can more easily come apart. When two heated molecules contain a more labile H atom and OH group and are close together, they can thus form even stronger inter-molecular covalent bonds while expelling a water molecule. And at elevated temperatures, the volatile H2O molecule is quickly driven off, leaving a less volatile larger or polymeric molecule as the remaining reaction product. Besides condensation polymer formation, cyclic anhydrides of varying compositions could also be a common class of reaction products occurring from dehydrating conditions.

Thus our increasingly complex pool of abiotically generated molecules all began from some very common, simple, low molecular weight and universally available starter molecules. All types of natural energy sources supplied the necessary energy to break simpler compounds into reactive fragments and allow those fragments to rearrange and reform into more complex and larger molecules. The process occurred over and over. Different elements became caught up in various locations within these molecular card shuffles. Hetero-atomic molecules brought a greater diversity of characteristics and capabilities to the growing morass. With the increasing complexities of the resultant mixtures, low probability events became more likely to occur. Certain combinations of molecules found themselves more closely associated with one another than the vast majority of the mixture components. Some of those closer associations had catalytic capabilities that when the associated chemical reactions occurred, the products of those coordinated reaction sequences generated more molecules of the same types. When those complexes continued to generate more of their own types, a Darwinian-like molecular competition occurred in which one very well-established survival pattern was born. Those complexes continued evolving at the expense of the less capable molecular species surrounding them. Non-self propagating molecular species began to break down in thermal and non-thermal bond dissociation events leading to their atoms becoming recycled into the growing populations of self-propagators. It was the molecular analog of a predator-prey pattern, and helped to clear the early environment of non-useful molecular species that did not provide any useful paths to a greater level of overall collaborative organization. What is meant by that is that in ecological terms, we have food chains that have been established over time through evolutionary refinements. The biosphere is considered a complete, self-sustaining system. Such was not the case at the molecular level just after the appearance of self-propagating molecular complexes and their associated chemistries. The less useful molecular species were cleared out while the survivors perfected their higher level coordination of structure.

Next: Pre-Biotic Evolution. Part II. Pre-Biotic Chemical Oscillations and Linked Reaction Sequences

* Scientific and Forensic Services, Inc., Delray Beach, FL. and Norfolk, VA scientificandforensicservices@gmail.com

References

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13. Kerridge J. F. (1991) A Note On The Prebiotic Synthesis Of Organic Acids In Carbonaceous Meteorites. Orig. Life Evol. Biosph.  21(1): 19-29.

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18. Maude, S., L. Tai, R. Davies, B. Liu, S. Harris, P. Kocienski, and A. Aggeli. Peptide Synthesis and Self-Assembly. In Top. Curr. Chem. “Peptide-Based Materials”. Ed. by T. Deming. pp. 27-70. Springer-Verlag, Berlin. (2012)

19. Cheng, J., and T. J. Deming. Synthesis of Polypeptides by Ring Opening Polymerization of α-Amino Acid N-Carboxyanhydrides. In Top. Curr. Chem. “Peptide-Based Materials”. Ed. by T. Deming. pp. 1-26. Springer-Verlag, Berlin. (2012)

20. Deamer, D., S. Singaram, S. Rajamani, V. Kompanichenko and S. Guggenheim. Self-Assembly Processes in the Pre-Biotic Environment. (2006) Phil. Trans. R. Soc. B 361: 1809-18

21. Merrifield, R. B. (1963) Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. J. Am. Chem. Soc. 85: 2149-2154

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23. Corbett, P., J. Leclaire, L. Vial, K. West, J. Wietor, J. Sanders, and S. Otto, (Sep 2006) Dynamic combinatorial chemistry. Chem. Rev. 106 (9): 3652–3711.

24. Lehn, J. (2007) From supramolecular chemistry towards constitutional dynamic chemistry and adaptive chemistry. Chem. Soc. Rev. 36: 151 – 160

© Copyrighted by Joseph H. Guth, 2014. All rights reserved.

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