Assembly Theory for Folded Matter

The transition in biochemistry, from synthesizing information directly into small-molecule structure, to imprinting it in the sequences of monomer “letters” in macromolecular strings, arguably reflects a reset in the evolutionary problem of harnessing complexity as molecular size increases. The property of macromolecules that enables this reset is the ability of all the major classes (proteins, RNA, DNA, poly-sugars) to form folds: compact geometrically regular structures formed by repeating the same local molecular geometries and contacts recursively. The breakout from small molecules to macromolecules in the origin of life occurred through the emergence of folded matter.

This working group will study the evolutionary dynamics of folded matter, introducing the framework of Assembly Theory to extract minimum-information hierarchies of the building blocks of folds. Assembly hierarchies will inform our understanding of the emergence and descent of a given fold with patterns of use, reuse, and association of its elements across much larger spaces of known structures than the intra-family comparisons currently used to reconstruct fold histories. The application of assembly ideas to folded matter will also extend the scope of Assembly Theory as a program, requiring us to recognize the elementary units and composition operations, self-consistently with the assembly trees they generate, incorporating external knowledge from comparative methods and constraints from the dynamics of folding itself. Our goal is to understand how folding enabled the taming of complexity against the computational difficulty of navigating expanding combinatorial molecular spaces.