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  1. Many organisms can survive extreme conditions and successfully recover to normal life. This extremotolerant behavior has been attributed in part to repetitive, amphipathic, and intrinsically disordered proteins that are upregulated in the protected state. Here, we assemble a library of approximately 300 naturally-occurring and designed extremotolerance-associated proteins to assess their ability to protect human cells from chemically-induced apoptosis. We show that several proteins from tardigrades, nematodes, and the Chinese giant salamander are apoptosis protective. Notably, we identify a region of the human ApoE protein with similarity to extremotolerance-associated proteins that also protects against apoptosis. This region mirrors the phase separationmore »behavior seen with such proteins, like the tardigrade protein CAHS2. Moreover, we identify a synthetic protein, DHR81, that shares this combination of elevated phase separation propensity and apoptosis protection. Finally, we demonstrate that driving protective proteins into the condensate state increases apoptosis protection, and highlight the ability for DHR81 condensates to sequester caspase-7. Taken together, this work draws a link between extremotolerance-associated proteins, condensate formation, and designing human cellular protection.« less
    Free, publicly-accessible full text available February 8, 2023
  2. Abstract Nucleation is generally viewed as a structural fluctuation that passes a critical size to eventually become a stable emerging new phase. However, this concept leaves out many details, such as changes in cluster composition and competing pathways to the new phase. In this work, both experimental and computer modeling studies are used to understand the cluster composition and pathways. Monte Carlo and molecular dynamics approaches are used to analyze the thermodynamic and kinetic contributions to the nucleation landscape in barium silicate glasses. Experimental techniques examine the resulting polycrystals that form. Both the modeling and experimental data indicate that amore »silica rich core plays a dominant role in the nucleation process.« less
    Free, publicly-accessible full text available December 1, 2022
  3. Free, publicly-accessible full text available December 1, 2022
  4. Elgar, Mark A. (Ed.)
    Coevolution—reciprocal evolutionary change between interacting lineages (Thompson, 1994; see Glossary)—is thought to have played a profound role in the evolution of Life on Earth. From similar patterns across the wings of unrelated lineages of butterflies (Hoyal Cuthill and Charleston, 2015), egg mimicry of “cheating” brood parasites (Davies, 2010), to the role of animal pollinators in driving the diversification of flowering plants (Kay and Sargent, 2009), to the ubiquity of sexual reproduction and sexual conflicts (Hamilton, 2002; Arnqvist and Rowe, 2005; King et al., 2009), the formation of the eukaryotic cell (Martin et al., 2015; Imachi et al., 2020), and evenmore »the origin of living organisms themselves (Mizuuchi and Ichihashi, 2018), evolutionary changes among interacting lineages have played profound and important roles in the history of Life. This Grand Challenges inaugural contribution encompasses eclectic opinions of the editorial board as to what are the next frontiers of coevolution research in the 21st century. Coevolutionary biology is a field that has garnered a lot of attention in recent years, in part as a result of technical advances in nucleotide sequencing and bioinformatics in the burgeoning field of host–microbial interactions. Many seminal studies of coevolution examined reciprocal evolutionary change between two or a few interacting macroscopic species that imposed selective pressures on one another (e.g., insect or bird pollinators and their flowering host plants). Understanding the contexts under which coevolution occurs, as opposed to scenarios in which each partner adapts independently to a particular environment (Darwin, 1862; Stiles, 1978) is important to elucidate coevolutionary processes. A whole spectrum of organismal interactions has been examined under the lens of coevolution, providing additional context, and nuance to ecological strategies traditionally categorized as ranging from beneficial to detrimental for participating species (Figure 1). In particular, a coevolutionary perspective has revealed that even “mutualisms” are not always fully beneficial or cooperative for the partners involved. Instead, the tendency to “cheat” permeates across symbiotic partnerships (Perez-Lamarque et al., 2020). Conversely, recent evidence suggests that non-lethal predation by co-evolved predators, which has traditionally been assumed to be entirely antagonistic, may provide sessile prey with some indirect benefit through enhanced opportunities to acquire beneficial symbiotic microorganisms (Grupstra et al., 2021). Herein, we discuss some of the recent areas of active research in coevolution, restricting our focus to coevolution between interacting species.« less
    Free, publicly-accessible full text available January 6, 2023
  5. Recent advances in synthetic posttranslational protein circuits are substantially impacting the landscape of cellular engineering and offer several advantages compared to traditional gene circuits. However, engineering dynamic phenomena such as oscillations in protein-level circuits remains an outstanding challenge. Few examples of biological posttranslational oscillators are known, necessitating theoretical progress to determine realizable oscillators. We construct mathematical models for two posttranslational oscillators, using few components that interact only through reversible binding and phosphorylation/dephosphorylation reactions. Our designed oscillators rely on the self-assembly of two protein species into multimeric functional enzymes that respectively inhibit and enhance this self-assembly. We limit our analysis tomore »within experimental constraints, finding (i) significant portions of the restricted parameter space yielding oscillations and (ii) that oscillation periods can be tuned by several orders of magnitude using recent advances in computational protein design. Our work paves the way for the rational design and realization of protein-based dynamic systems.« less
  6. Free, publicly-accessible full text available October 27, 2022
  7. Abstract

    A systematic and robust approach to generating complex protein nanomaterials would have broad utility. We develop a hierarchical approach to designing multi-component protein assemblies from two classes of modular building blocks: designed helical repeat proteins (DHRs) and helical bundle oligomers (HBs). We first rigidly fuse DHRs to HBs to generate a large library of oligomeric building blocks. We then generate assemblies with cyclic, dihedral, and point group symmetries from these building blocks using architecture guided rigid helical fusion with new software named WORMS. X-ray crystallography and cryo-electron microscopy characterization show that the hierarchical design approach can accurately generate amore »wide range of assemblies, including a 43 nm diameter icosahedral nanocage. The computational methods and building block sets described here provide a very general route tode novodesigned protein nanomaterials.

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