The solution of the “protein folding problem” is critical to the burgeoning field of protein engineering and design. In this review, we discuss some developments that prompt us to seek an explicit stereochemical code for protein assembly. Our analysis leads to the conclusion that, to a good approximation, protein molecules are structural hierarchies of just four types of primitive folding units-including a novel unit called the Ω-loop. This conclusion, in turn, suggests a model of protein assembly called hierarchic condensation in which these nascent structural primitives associate in step-wise fashion, leading to larger modules and further association. Hierarchic organization is a familiar and simplifying pattern in the macroscopic world, so the existence of hierarchic architecture in proteins is a tantalizing finding. Despite their apparent structural complexity, protein molecules may yet turn out to be governed by stereochemical rules that are remarkably simple.
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