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An assembly funnel makes biomolecular complex assembly efficient.

Zenk J, Schulman R - PLoS ONE (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.

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.

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Design of components so that particular assembly pathways are favored can drastically increase assembly yields.(a) Schematic of spiral complex assembly via the favored assembly pathway. On the favored assembly pathway, assembly begins with the “L” shaped component, labeled “1”. At each assembly step, a component attaches through two interfaces (following the green arrow). Other components can only attach through one. Lengths of reaction arrows indicate propensities in the assembly funnel regime. Assembly yields for a (b) 2×2 (4 component), (c) 3×3 (9 component) and (d) 4×4 (16 component) spiral complex as a function of a dimensionless temperature parameter, . Inset diagram depicts the complex and numbers on the components in the complex indicate component identity. Colored bars below the figure represent the four different assembly regimes for spiral complexes and grid complexes containing the same number of components. Error bars <1%.
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pone-0111233-g006: Design of components so that particular assembly pathways are favored can drastically increase assembly yields.(a) Schematic of spiral complex assembly via the favored assembly pathway. On the favored assembly pathway, assembly begins with the “L” shaped component, labeled “1”. At each assembly step, a component attaches through two interfaces (following the green arrow). Other components can only attach through one. Lengths of reaction arrows indicate propensities in the assembly funnel regime. Assembly yields for a (b) 2×2 (4 component), (c) 3×3 (9 component) and (d) 4×4 (16 component) spiral complex as a function of a dimensionless temperature parameter, . Inset diagram depicts the complex and numbers on the components in the complex indicate component identity. Colored bars below the figure represent the four different assembly regimes for spiral complexes and grid complexes containing the same number of components. Error bars <1%.

Mentions: While it is challenging to optimize reaction conditions to produce high yields, might it be possible to create components that broaden the assembly funnel regime and thus self-assemble a desired complex more efficiently? To address this question, we designed components for a 2-dimensional target structure that were expected to have a smaller barrier to nucleation than the components of the grid complex we studied above. In a “spiral complex,” a spiral-shaped growth pathway allows all components to attach to the growing assembly via multiple bonds, so that there is no nucleation barrier to assembly. Because all other growth pathways require that components interact with one another via a single bond, the single spiral-shaped growth pathway is favored (Fig. 6a). Compared to square grid complex counterparts, the 4-, 9- and 16-component spiral complexes assemble faster and even achieve thermodynamic equilibrium in nucleation-limited regimes, broadening the reaction conditions that generate an assembly funnel (Fig. 6b–d). As a result, an anneal produces complexes more quickly, by almost an order of magnitude (Figs. S11 and S12). While the spiral scheme does not improve yield in the rearrangement-limited regime, this exercise suggests that effective self-assembly design strategies will likely promote rapid, high-yield complex formation by considering reaction pathways as well as nucleation and rearrangement rates.


An assembly funnel makes biomolecular complex assembly efficient.

Zenk J, Schulman R - PLoS ONE (2014)

Design of components so that particular assembly pathways are favored can drastically increase assembly yields.(a) Schematic of spiral complex assembly via the favored assembly pathway. On the favored assembly pathway, assembly begins with the “L” shaped component, labeled “1”. At each assembly step, a component attaches through two interfaces (following the green arrow). Other components can only attach through one. Lengths of reaction arrows indicate propensities in the assembly funnel regime. Assembly yields for a (b) 2×2 (4 component), (c) 3×3 (9 component) and (d) 4×4 (16 component) spiral complex as a function of a dimensionless temperature parameter, . Inset diagram depicts the complex and numbers on the components in the complex indicate component identity. Colored bars below the figure represent the four different assembly regimes for spiral complexes and grid complexes containing the same number of components. Error bars <1%.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4215988&req=5

pone-0111233-g006: Design of components so that particular assembly pathways are favored can drastically increase assembly yields.(a) Schematic of spiral complex assembly via the favored assembly pathway. On the favored assembly pathway, assembly begins with the “L” shaped component, labeled “1”. At each assembly step, a component attaches through two interfaces (following the green arrow). Other components can only attach through one. Lengths of reaction arrows indicate propensities in the assembly funnel regime. Assembly yields for a (b) 2×2 (4 component), (c) 3×3 (9 component) and (d) 4×4 (16 component) spiral complex as a function of a dimensionless temperature parameter, . Inset diagram depicts the complex and numbers on the components in the complex indicate component identity. Colored bars below the figure represent the four different assembly regimes for spiral complexes and grid complexes containing the same number of components. Error bars <1%.
Mentions: While it is challenging to optimize reaction conditions to produce high yields, might it be possible to create components that broaden the assembly funnel regime and thus self-assemble a desired complex more efficiently? To address this question, we designed components for a 2-dimensional target structure that were expected to have a smaller barrier to nucleation than the components of the grid complex we studied above. In a “spiral complex,” a spiral-shaped growth pathway allows all components to attach to the growing assembly via multiple bonds, so that there is no nucleation barrier to assembly. Because all other growth pathways require that components interact with one another via a single bond, the single spiral-shaped growth pathway is favored (Fig. 6a). Compared to square grid complex counterparts, the 4-, 9- and 16-component spiral complexes assemble faster and even achieve thermodynamic equilibrium in nucleation-limited regimes, broadening the reaction conditions that generate an assembly funnel (Fig. 6b–d). As a result, an anneal produces complexes more quickly, by almost an order of magnitude (Figs. S11 and S12). While the spiral scheme does not improve yield in the rearrangement-limited regime, this exercise suggests that effective self-assembly design strategies will likely promote rapid, high-yield complex formation by considering reaction pathways as well as nucleation and rearrangement rates.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.

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.

Show MeSH
Related in: MedlinePlus