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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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The amount of bond coupling, or additivity of bond energies during cooperative binding steps does not significantly affect assembly yields above a small threshold.Yield of a 3×3 square grid complex as a function of the bond coupling constant,  under many isothermal assembly conditions (solid lines, color) and after an anneal (black) for reaction time . Dashed lines show yields at thermodynamic equilibrium for isothermal conditions with the same color. Error bars <1%.
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pone-0111233-g005: The amount of bond coupling, or additivity of bond energies during cooperative binding steps does not significantly affect assembly yields above a small threshold.Yield of a 3×3 square grid complex as a function of the bond coupling constant, under many isothermal assembly conditions (solid lines, color) and after an anneal (black) for reaction time . Dashed lines show yields at thermodynamic equilibrium for isothermal conditions with the same color. Error bars <1%.

Mentions: 2- and 3-dimensional complexes are generally stabilized by the interactions of multiple bonds between components, and the specific free energy changes that result from multi-bond interactions also shape the energy landscape for assembly [45]. To determine how the free energy of multi-bond interactions influences yield, we characterized changes in yield as we altered the coupling between multiple interfaces on a component. Surprisingly, we found that bond coupling was not an important determinant of assembly yield (see Fig. 5 and Figs. S7, S21). Although positive coupling () slightly broadens the set of conditions where complex yields are high at thermodynamic equilibrium (Figs. S6, S20), it leads neither to increased nucleation rates nor component rearrangement rates and thus does not increase yields in practice. Negative coupling () does not always reduce yields in the assembly funnel regime and can even marginally enhance yields under rearrangement-limited isothermal conditions by destabilizing some intermediates (Text S5). Thus, high-yield assembly can be obtained under the proper assembly conditions for a wide range of bond coupling values, as any coupling value is subject to equal pressures on nucleation and rearrangement rates.


An assembly funnel makes biomolecular complex assembly efficient.

Zenk J, Schulman R - PLoS ONE (2014)

The amount of bond coupling, or additivity of bond energies during cooperative binding steps does not significantly affect assembly yields above a small threshold.Yield of a 3×3 square grid complex as a function of the bond coupling constant,  under many isothermal assembly conditions (solid lines, color) and after an anneal (black) for reaction time . Dashed lines show yields at thermodynamic equilibrium for isothermal conditions with the same color. Error bars <1%.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111233-g005: The amount of bond coupling, or additivity of bond energies during cooperative binding steps does not significantly affect assembly yields above a small threshold.Yield of a 3×3 square grid complex as a function of the bond coupling constant, under many isothermal assembly conditions (solid lines, color) and after an anneal (black) for reaction time . Dashed lines show yields at thermodynamic equilibrium for isothermal conditions with the same color. Error bars <1%.
Mentions: 2- and 3-dimensional complexes are generally stabilized by the interactions of multiple bonds between components, and the specific free energy changes that result from multi-bond interactions also shape the energy landscape for assembly [45]. To determine how the free energy of multi-bond interactions influences yield, we characterized changes in yield as we altered the coupling between multiple interfaces on a component. Surprisingly, we found that bond coupling was not an important determinant of assembly yield (see Fig. 5 and Figs. S7, S21). Although positive coupling () slightly broadens the set of conditions where complex yields are high at thermodynamic equilibrium (Figs. S6, S20), it leads neither to increased nucleation rates nor component rearrangement rates and thus does not increase yields in practice. Negative coupling () does not always reduce yields in the assembly funnel regime and can even marginally enhance yields under rearrangement-limited isothermal conditions by destabilizing some intermediates (Text S5). Thus, high-yield assembly can be obtained under the proper assembly conditions for a wide range of bond coupling values, as any coupling value is subject to equal pressures on 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