Recent Articles
Synthetic chemistry recreates transitional forms in prebiotic membrane evolution
Membranes are an essential part of living systems. Today’s phospholipid membranes are believed to have originated as spontaneously self-assembled fatty acid membranes billions of years ago. How might the transition to phospholipids occur? In this issue of Chem, Pulletikurti et al. recreate transitional forms based on prebiotic chemical reactions, filling in “missing links” of early membrane evolution.
Effect of montmorillonite K10 clay on RNA structure and function
Biophysical Journal 123 (2023), 451
Life on earth is believed to have progressed through an intermediate stage in which RNA took on multiple roles, including genetic material and biocatalysts. It has been suggested that certain clay minerals, such as montmorillonite, may have facilitated the emergence of RNA-based life by promoting chemical processes and enforcing spatial segregation that limited the spread of parasitic sequences. At the same time, interactions between a mineral surface and adsorbed RNA are expected to perturb RNA structure and function. Here we studied the effect of montmorillonite on the folding of model oligonucleotides, including an aptamer. While some base-pairing interactions were preserved, tertiary structure and function were disrupted by montmorillonite. The results indicate that mineral association would constrain an RNA world.
Modulation of α-Synuclein Aggregation In Vitro by a DNA Aptamer
Protein aggregation is an important problem for human health and biotechnology, Methods to modulate protein aggregation are therefore essential. One suggested method to modulate protein aggregation is the use of nucleic acid aptamers, that is, single-stranded nucleic acids that have been selected to specifically bind to a target. Previous studies in some systems have demonstrated that aptamers may inhibit protein aggregation, including for α-synuclein, a protein implicated in synucleinopathies. However, the mechanisms by which aptamers might affect or modulate aggregation have not been fully determined. In this study, we investigated the effect of an aptamer that binds α-synuclein oligomer, T-SO508, on α-synuclein aggregation in vitro using thioflavin T to monitor aggregation kinetics, and we performed atomic force microscopy, transmission electron microscopy, and analytical ultracentrifugation to characterize intermediate structures. The results indicated that T-SO508, but not control DNA sequences, extends the lag phase of aggregation and stabilizes formation of a small non-fibrillar aggregate complex. Attempts to use the aptamer-induced complexes to seed fibril formation did not in fact accelerate aggregation, indicating that these structures are off-pathway for aggregation. This study highlights a potential mechanism by which aptamers may modulate the aggregation properties of proteins.
Effect of UV Radiation on Fluorescent RNA Aptamers’ Functional and Templating Ability
UV damage to functional RNAs has been relatively little studied. We irradiated two fluorescent RNA aptamers and monitored the loss of activity, folding, and the kinetics of lesion accumulation. UV susceptibility was highly heterogeneous across the RNA sites; this indicates the importance of UV exposure as a selective pressure during the origin of life.
Molecular Fitness Landscapes from High-Coverage Sequence Profiling
The function of fitness (or molecular activity) in the space of all possible sequences is known as the fitness landscape. Evolution is a random walk on the fitness landscape, with a bias toward climbing hills. Mapping the topography of real fitness landscapes is fundamental to understanding evolution, but previous efforts were hampered by the difficulty of obtaining large, quantitative data sets. The accessibility of high-throughput sequencing (HTS) has transformed this study, enabling large-scale enumeration of fitness for many mutants and even complete sequence spaces in some cases. We review the progress of high-throughput studies in mapping molecular fitness landscapes, both in vitro and in vivo, as well as opportunities for future research. Such studies are rapidly growing in number. HTS is expected to have a profound effect on the understanding of real molecular fitness landscapes.
Lipid vesicles chaperone an encapsulated RNA aptamer
The organization of molecules into cells is believed to have been critical for the emergence of living systems. Early protocells likely consisted of RNA functioning inside vesicles made of simple lipids. However, little is known about how encapsulation would affect the activity and folding of RNA. Here we find that confinement of the malachite green RNA aptamer inside fatty acid vesicles increases binding affinity and locally stabilizes the bound conformation of the RNA. The vesicle effectively ‘chaperones’ the aptamer, consistent with an excluded volume mechanism due to confinement. Protocellular organization thereby leads to a direct benefit for the RNA. Coupled with previously described mechanisms by which encapsulated RNA aids membrane growth, this effect illustrates how the membrane and RNA might cooperate for mutual benefit. Encapsulation could thus increase RNA fitness and the likelihood that functional sequences would emerge during the origin of life.
Origin of Life: Protocells Red in Tooth and Claw
To study the origin of life, synthetic biologists construct simple ‘protocells’, but previous models were not able to reproduce both genome and membrane sustainably. A recent advance feeds the protocells by vesicle fusion, suggesting a practical pathway for indefinite self-reproduction.
Molecular crowding and early evolution
The environment of protocells might have been crowded with small molecules and functional and non-specific polymers. In addition to altering conformational equilibria, affecting reaction rates and changing the structure and activity of water, crowding might have enhanced the capabilities of protocells for evolutionary innovation through the creation of extended neutral networks in the fitness landscape.