Abstract
Like protein folding and crystallization, the self-assembly of complexes is a fundamental form of biomolecular organization. While the number of methods for creating synthetic complexes is growing rapidly, most require empirical tuning of assembly conditions and/or produce low yields. We use coarse-grained simulations of the assembly kinetics of complexes to identify generic limitations on yields that arise because of the many simultaneous interactions allowed between the components and intermediates of a complex. Efficient assembly occurs when nucleation is fast and growth pathways are few, i.e. when there is an assembly “funnel”. For typical complexes, an assembly funnel occurs in a narrow window of conditions whose location is highly complex specific. However, by redesigning the components this window can be drastically broadened, so that complexes can form quickly across many conditions. The generality of this approach suggests assembly funnel design as a foundational strategy for robust biomolecular complex synthesis.
Highlights
Within cells, bottom-up phenomena organize biomolecules into structures with sizes ranging from angstroms to microns
Most existing strategies for the design and analysis of selfassembly processes use the thermodynamics of a complex as a starting point for predicting structure and yield
This strategy has been successful for understanding the assembly process of homogeneous or periodic crystals and superlattices [46]
Summary
Bottom-up phenomena organize biomolecules into structures with sizes ranging from angstroms to microns. Larger biomolecular structures orchestrate processes such as translation, adhesion, or controlled transport. Stable nanometer- or angstrom-scale structures generally form as the result of folding a protein or RNA chain with a particular sequence [2]. Larger structures instead form through a hierarchical assembly process in which folded components self-assemble together into a larger complex. Examples of such complexes include the ribosome, proteasome and antibodies. Some complexes, including the nuclear pore complex [10], cell adhesions [11] or the kinetochore [12] can contain hundreds of components and reach sizes of more than a micron. Complex formation is ubiquitous: in Escherichia coli, for example, more than 20% of known polypeptides become reported members of protein complexes [13]
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