Loren Dean Williams

• PhD
• Professor (Full) at Georgia Institute of Technology

A general framework for conventional models of the origin of life (OOL) is the specification of a ‘privileged function.’ A privileged function is an extant biological function that is excised from its biological context, elevated in importance over other functions, and transported back in time to a primitive chemical or geological environment. In R...

The ribosome is imprinted with a detailed molecular chronology of the origins and early evolution of proteins. Here we show that when arranged by evolutionary phase of ribosomal evolution, ribosomal protein (rProtein) segments reveal an atomic level history of protein folding. The data support a model in which aboriginal oligomers evolved into glob...

Significance The ribosome, in analogy with a tree, contains a record of its history, spanning 4 billion years of life on earth. The information contained within ribosomes connects us to the prehistory of biology. Details of ribosomal RNA variation, observed by comparing three-dimensional structures of ribosomes across the tree of life, form the bas...

In a model describing the origin and evolution of the translation system, ribosomal RNA (rRNA) grew in size by accretion [Petrov et al., (2015) "History of the Ribosome and the Origin of Translation", Proc. Natl. Acad. Sci. U.S.A. 112, 15396-15401]. Large rRNAs were built up by iterative incorporation and encasement of small folded RNAs. In this mo...

Significance Ribosomes exist in every cell and are responsible for translation from mRNA to protein. The structure of the ribosomal common core is highly conserved in all living species, while the outer regions of the ribosome are variable. Ribosomal RNA of eukaryotes contains expansion segments accreted onto the surface of the core, which is nearl...

Many open questions about the origins of life are centred on the generation of complex chemical species. Past work has characterized specific chemical reactions that might lead to biological molecules. Here we establish an experimental model of chemical evolution to investigate general processes by which chemical systems continuously change. We use...

RNA secondary (2D) structure visualization is an essential tool for understanding RNA function. R2DT is a software package designed to visualize RNA 2D structures in consistent, recognizable, and reproducible layouts. The latest release, R2DT 2.0, introduces multiple significant features, including the ability to display position-specific informati...

The β and β′ subunits of the RNA polymerase (RNAP) are large proteins with complex multi‐domain architectures that include several insertional domains. Here, we analyze the domain organizations of RNAP‐β and RNAP‐β′ using sequence, experimentally determined structures and AlphaFold structure predictions. We observe that lineage‐specific insertional...

Conspectus The mystery of the origins of life is one of the most difficult yet intriguing challenges to which humanity has grappled. How did biopolymers emerge in the absence of enzymes (evolved biocatalysts), and how did long-lasting chemical evolution find a path to the highly selective complex biology that we observe today? In this paper, we di...

RNA secondary (2D) structure visualisation is an essential tool for understanding RNA function. R2DT is a software package designed to visualise RNA 2D structures in consistent, recognisable, and reproducible layouts. The latest release, R2DT 2.0, introduces multiple significant features, including the ability to display position-specific informati...

The emergence of chemical selectivity presents one of the greatest challenges in the origins-of-life research. Complex or even relatively simple chemical mixtures undergoing chemical transformations tend to combinatorically explode. Large numbers of different chemical products arise because of the large number of ways by which mixtures of reactants...

The β and β’ subunits of the RNA polymerase (RNAP) are large proteins with complex multi-domain architectures that include several insertional domains. Here, we analyze the multi-domain organizations of bacterial RNAP-β and RNAP-β’ using sequence, experimentally determined structures and AlphaFold structure predictions. We observe that bacterial li...

Aminoacyl‐tRNA synthetases (aaRSs) establish the genetic code. Each aaRS covalently links a given canonical amino acid to a cognate set of tRNA isoacceptors. Glycyl tRNA aminoacylation is unusual in that it is catalyzed by different aaRSs in different lineages of the Tree of Life. We have investigated the phylogenetic distribution and evolutionary...

Some of the most interesting open questions about the origins of life and molecular sciences center on chemical evolution and the spontaneous generation of complex and functional chemical species. The processes that generated the spectacular biopolymers that underlay biology demonstrate an untapped, by modern science, creative potential. We have es...

The origins of biopolymers pose some of the most fascinating questions in prebiotic chemistry. The marvelous assembly proficiencies of biopolymers suggest they are winners of a competitive evolutionary process. Molecular assembly is ubiquitous in life and in abiotic systems and is often emergent upon polymerization. We focus on the influence of mol...

Complex or even relatively simple mixtures undergoing chemical transformations tend to combinatorically explode, i.e., a large number of different chemical species arise due to the large number of ways to combine them. The rise of chemical selectivity was one of the most important steps towards life and its emergence presents one of the most challe...

Progress in understanding the origins of life will be enhanced if models and their predictions are clearly understood and explicitly articulated. Two distinct models can be used to explain the genesis of biopolymers during the origins of life. In one model, which has been pursued for nearly 50 years, RNA is the result of inherent chemical reactivit...

Glycyl tRNA aminoacylation is catalyzed by different enzymes in different lineages of the Tree of Life. The archaeal (arcGlyRS) and bacterial (bacGlyRS) versions of glycyl tRNA synthetase are globally different. arcGlyRS is a relatively small protein with two domains: a catalytic domain and a tRNA recognition domain. bacGlyRS is a large, multi-doma...

The synthesis capabilities of the translation system (TS) provide engineering and directed evolution potential as well as a system for generating novel polymers. Orthogonal translation systems offer a parallel platform for translation engineering, enabling primary and secondary translation systems to operate independently without interfering with e...

Magnesium, the most abundant divalent cation in cells, catalyzes RNA cleavage but also promotes RNA folding. Because folding can protect RNA from cleavage, we predicted a 'Goldilocks landscape', with local maximum in RNA lifetime at Mg2+ concentrations required for folding. Here, we use simulation and experiment to discover an innate and sophistica...

Heme b (iron protoporphyrin IX) plays important roles in biology as a metallocofactor and signaling molecule. However, the targets of heme signaling and the network of proteins that mediate the exchange of heme from sites of synthesis or uptake to heme dependent or regulated proteins are poorly understood. Herein, we describe a quantitative mass sp...

Mechanisms of emergence and divergence of protein folds pose central questions in biological sciences. Incremental mutation and stepwise adaptation explain relationships between topologically similar protein folds. However, the universe of folds is diverse and riotous, suggesting more potent and creative forces are at play. Sequence and structure s...

Heme b (iron protoporphyrin IX) plays important roles in biology as a metallocofactor and signaling molecule. However, the targets of heme signaling and the network of proteins that mediate the exchange of heme from sites of synthesis or uptake to heme dependent or regulated proteins are poorly understood. Herein, we describe a quantitative mass sp...

The ribosomal core is universally conserved across the tree of life. However, eukaryotic ribosomes contain diverse rRNA expansion segments (ESs) on their surfaces. Sites of ES insertions are predicted from sites of insertion of micro-ESs in archaea. Expansion segment 7 (ES7) is one of the most diverse regions of the ribosome, emanating from a short...

Aerobic respiration evolved by bricolage, with modules cobbled together as microbial biochemistry coevolved with Earth’s geochemistry. The mitochondrial electron transport chain represents a patchwork of respiratory modules inherited from microbial methanogenesis, iron oxidation, anoxygenic photosynthesis, and denitrification pathways, and preserve...

The Prebiotic Chemistry and Early Earth Environments (PCE3) Consortium is a community of researchers seeking to understand the origins of life on Earth and in the universe. PCE3 is one of five Research Coordination Networks (RCNs) within NASA’s Astrobiology Program. Here we report on the inaugural PCE3 workshop, intended to cross-pollinate, transfe...

Some of the most interesting open questions about the origins of life and molecular sciences center on chemical evolution and the spontaneous generation of new complex and functional chemical species. The spectacular polymers that underlay biology demonstrate an untapped, by modern science, creative potential. We hypothesized that prebiotic chemica...

The high kinetic barrier to amide bond formation has historically placed narrow constraints on its utility in reversible chemistry applications. Slow kinetics has limited the use of amides for the generation of diverse combinatorial libraries and selection of target molecules. Current strategies for peptide-based dynamic chemistries require the use...

Some of the most interesting open questions about the origins of life and molecular sciences center on chemical evolution and the spontaneous generation of new complex and functional chemical species. The spectacular polymers that underlay biology demonstrate an untapped, by modern science, creative potential. We hypothesized that prebiotic chemica...

It is widely assumed that the condensation of building blocks into oligomers and polymers was important in the origins of life. High activation energies, unfavorable thermodynamics and side reactions are bottlenecks for abiotic peptide formation. All abiotic reactions reported thus far for peptide bond formation via thioester intermediates have rel...

Evolution works by adaptation and exaptation. At an organismal level, exaptation and adaptation are seen in the formation of organelles and the advent of multicellularity. At the sub-organismal level, molecular systems such as proteins and RNAs readily undergo adaptation and exaptation. Here we suggest that the concepts of adaptation and exaptation...

Mechanisms by which new protein folds emerge and diverge pose central questions in biological sciences. Incremental mutation and step-wise adaptation explain relationships between topologically similar protein folds. However, the universe of folds is diverse and riotous, suggesting roles of more potent and creative forces. Sequence and structure si...

The origin of biopolymers is a central question in origins of life research. In extant life, proteins are coded linear polymers made of a fixed set of twenty alpha-L-amino acids. It is likely that the prebiotic forerunners of proteins, or protopeptides, were more heterogenous polymers with a greater diversity of building blocks and linkage stereoch...

We have developed the program TwinCons, to detect noisy signals of deep ancestry of proteins or nucleic acids. As input, the program uses a composite alignment containing pre-defined groups, and mathematically determines a ‘cost’ of transforming one group to the other at each position of the alignment. The output distinguishes conserved, variable a...

SH3 and OB are the simplest, oldest and most common protein domains within the translation system. SH3 and OB domains are β-barrels that are structurally similar but are topologically distinct. To transform an OB domain to a SH3 domain, β-strands must be permuted in a multistep and evolutionarily implausible mechanism. Here, we explored relationshi...

Mg ²⁺ , the most abundant divalent cation in cells, catalyzes RNA cleavage but can also promote RNA folding. Because folding can protect RNA from cleavage, we predicted a “Goldilocks zone”, which is a local maximum in RNA lifetime at the minimum Mg ²⁺ concentration required for folding. By simulation and experiment, we characterized the RNA Goldilo...

Non-coding RNAs (ncRNA) are essential for all life, and their functions often depend on their secondary (2D) and tertiary structure. Despite the abundance of software for the visualisation of ncRNAs, few automatically generate consistent and recognisable 2D layouts, which makes it challenging for users to construct, compare and analyse structures....

ProteoVision is a web server designed to explore protein structure and evolution through simultaneous visualization of multiple sequence alignments, topology diagrams and 3D structures. Starting with a multiple sequence alignment, ProteoVision computes conservation scores and a variety of physicochemical properties and simultaneously maps and visua...

The condensation of building blocks into oligomers and polymers was an early and important stage in the origins of life. High activation energies, unfavorable thermodynamics and side reactions are bottlenecks for abiotic formation of peptides. Thioesters are hypothesized to have played key roles in prebiotic chemistry on early Earth, serving as ene...

Transition metals enhance prebiotic proto-peptide oligomerization reactions through direct association with histidine.

Water, the most abundant compound on the surface of the Earth and probably in the universe, is the medium of biology, but is much more than that. Water is the most frequent actor in the chemistry of metabolism. Our quantitation here reveals that water accounts for 99.4% of metabolites in Escherichia coli by molar concentration. Between a third and...

Non-coding RNAs (ncRNA) are essential for all life, and the functions of many ncRNAs depend on their secondary (2D) and tertiary (3D) structure. Despite proliferation of 2D visualisation software, there is a lack of methods for automatically generating 2D representations in consistent, reproducible, and recognisable layouts, making them difficult t...

Widespread testing for the presence of the novel coronavirus SARS-CoV-2 in individuals remains vital for controlling the COVID-19 pandemic prior to the advent of an effective treatment. Challenges in testing can be traced to an initial shortage of supplies, expertise and/or instrumentation necessary to detect the virus by quantitative reverse trans...

The in vitro formation of stable G-quadruplexes (G4s) in human ribosomal RNA (rRNA) was recently reported. However, their formation in cells and their cellular roles were not resolved. Here, by taking a chemical biology approach that integrates results from immunofluorescence, G4 ligands, heme affinity reagents, and a genetically encoded fluorescen...

The ribosome's common core, comprised of ribosomal RNA (rRNA) and universal ribosomal proteins, connects all life back to a common ancestor and serves as a window to relationships among organisms. The rRNA of the common core is most similar to rRNA of extant bacteria. In eukaryotes, the rRNA of the common core is decorated by expansion segments (ES...

Any search for present or past life beyond Earth should consider the initial processes and related environmental controls that might have led to its start. As on Earth, such an understanding lies well beyond how simple organic molecules become the more complex biomolecules of life, because it must also include the key environmental factors that per...

Widespread testing for the presence novel coronavirus SARS-CoV-2 in patients remains vital for controlling the COVID-19 pandemic prior to the advent of an effective treatment. The early testing shortfall in some parts of the US can be traced to an initial shortage of supplies, expertise and/or instrumentation necessary to detect the virus by quanti...

Divalent metal cations are essential to the structure and function of the ribosome. Previous characterizations of the ribosome performed under standard laboratory conditions have implicated Mg2+ as a primary mediator of ribosomal structure and function. Possible contributions of Fe2+ as a ribosomal cofactor have been largely overlooked, despite the...

The close synergy between peptides and nucleic acids in current biology is suggestive of a functional co-evolution between the two polymers. Here we show that cationic proto-peptides (depsipeptides and polyesters), either produced as mixtures from plausibly prebiotic dry-down reactions or synthetically prepared in pure form, can engage in direct in...

The ribosome is an ancient molecular fossil that provides a telescope to the origins of life. Made from RNA and protein, the ribosome translates mRNA to coded protein in all living systems. Universality, economy, centrality and antiquity are ingrained in translation. The translation machinery dominates the set of genes that are shared as orthologue...

The in vitro formation of stable G-quadruplexes (G4s) in human ribosomal RNA (rRNA) was recently reported. However, their formation in cells and their cellular roles have not been resolved. Here, by taking a chemical biology approach that integrates results from immunofluorescence, G4 ligands, heme affinity reagents, and a genetically encoded fluor...

Cells continuously monitor protein synthesis to prevent accumulation of aberrant polypeptides. Insufficient capacity of cellular degradative systems, chaperone shortage or high levels of mistranslation by ribosomes can result in proteotoxic stress and endanger proteostasis. One of the least explored reasons for mistranslation is the incorrect funct...

The ribosome’s common core, comprised of ribosomal RNA (rRNA) and universal ribosomal proteins, connects all life back to a common ancestor and serves as a window to relationships among organisms. The rRNA of the common core is most similar to rRNA of extant bacteria. In eukaryotes, the rRNA of the common core is decorated by expansion segments (ES...

Mammalian and bird ribosomes are nearly twice the mass of prokaryotic ribosomes in part because of their extraordinarily long rRNA tentacles. Human rRNA tentacles are not fully observable in current three-dimensional structures and their conformations remain to be fully resolved. In previous work we identified sequences that favor G-quadruplexes in...

Divalent metal cations are essential to the structure and function of the ribosome. Previous characterizations of the ribosome performed under standard laboratory conditions have implicated Mg ²⁺ as a primary mediator of ribosomal structure and function. Possible contributions of Fe ²⁺ as a ribosomal cofactor have been largely overlooked, despite t...

Significance One of the long-standing questions in origins-of-life research centers on how the proteinaceous side chains and the protein backbone were selected during the earliest phases of evolution. Here we have studied oligomerization reactions of a group of positively charged amino acids, both proteinaceous and nonproteinaceous. Amino acids spo...

Life as we know it requires three basic types of polymers: polypeptide, polynucleotide, and polysaccharide. Here we evaluate both universal and idiosyncratic characteristics of these biopolymers. We incorporate this information into a model that explains much about their origins, selection, and early evolution. We observe that all three biopolymer...

Significance Ribosomes are found in every living organism, where they are responsible for the translation of messenger RNA into protein. The ribosome’s centrality to cell function is underscored by its evolutionary conservation; the core structure has changed little since its inception ∼4 billion years ago when ecosystems were anoxic and metal-rich...

Substantial similarities and profound differences mark ribosomes across phylogeny. The ribosomal core is universal, yet mammalian ribosomes are nearly twice as large as those of prokaryotes. This difference in size is predominantly due to the extension of specific rRNA regions called expansion segments. Here, we characterize expansion segment 7 of...

Today, Mg ²⁺ is an essential cofactor with diverse structural and functional roles in life’s oldest macromolecular machine, the translation system. We tested whether ancient Earth conditions (low O 2 , high Fe ²⁺ , high Mn ²⁺ ) can revert the ribosome to a functional ancestral state. First, SHAPE (Selective 2’ H ydroxyl A cylation analyzed by P rim...

Functions, origins, and evolution of the translation system are best understood in the context of unambiguous and phylogenetically based taxonomy and nomenclature. Here, we map ribosomal proteins onto the tree of life and provide a nomenclature for ribosomal proteins that is consistent with phylogenetic relationships. We have increased the accuracy...

There is broad consensus that during and immediately following the origin of life, RNA was the single biopolymer or was among a small group of cooperating biopolymers. During the origin of life, the Archean Earth was anoxic; Fe²⁺ was abundant and relatively benign. We hypothesize that RNA used Fe²⁺ as a cofactor instead of, or along with, Mg²⁺ duri...

Virus Like Particles (VLPs) are devices for RNA packaging, protection and delivery, with utility in fundamental research, drug discovery, and disease treatment. Using E. coli for combined expression and packaging of non-viral RNAs into Qβ VLPs, we investigated the extent of chemical protection conferred by packaging of RNA in VLPs. We also probed r...

The Universal Gene Set of Life (UGSL) is common to genomes of all extant organisms. The UGSL is small, consisting of less than 100 genes, and is dominated by genes encoding the translation system. Here we extend the search for biological universality to three dimensions. We characterize and quantitate the universality of structure of macromolecules...

Background Rotifers are microscopic aquatic invertebrates that reproduce both sexually and asexually. Though rotifers are phylogenetically distant from humans, and have specialized reproductive physiology, this work identifies a surprising conservation in the control of reproduction between humans and rotifers through the estrogen receptor. Until r...

The assembled bacterial ribosome contains around 50 proteins and many counterions. Here, focusing on rRNA from the large ribosomal subunit, we demonstrate that Mg²⁺ causes structural collapse in the absence of ribosomal proteins. The collapsed rRNA forms many native-like RNA–RNA interactions, similar to those observed in the assembled ribosome. We...

Diversity in eukaryotic rRNA structure and function offers possibilities of novel therapeutic targets. Unlike ribosomes of prokaryotes, eukaryotic ribosomes contain species-specific rRNA expansion segments (ESs) with idiosyncratic structures and functions that are essential and specific to some organisms. Here we investigate expansion segment 7 (ES...

As illustrated by the mitochondrion and the eukaryotic cell, little in biology makes sense except in light of mutualism. Mutualisms are persistent, intimate, and reciprocal exchanges; an organism proficient in obtaining certain benefits confers those on a partner, which reciprocates by conferring different benefits. Mutualisms (i) increase fitness,...