The free energy per monomer of a protein aggregate varies with the number of participating monomers n. The change of this free energy with aggregate size, ΔΔG(n), is difficult to determine by sedimentation or concentration studies. We introduce a kinetic approach to quantitate the free energy of aggregates in the presence of tethers. By linking the protein U1A into dimers and trimers, a high effective concentration of the monomers is achieved, together with exact size control of the aggregates. We found that the free energy of the aggregate relative to the native monomer reached a maximum for n = 2, and decreased by ΔΔG(2) = -3.1 kT between dimer and trimer.
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