In practice, TCA (trichloroacetic acid) is widely used for quantitative protein precipitation, but so far I have failed to discover the exact mechanism of TCA action. I highly doubt it's just the effect of pH that precipitates proteins. Any better guesses?


The paper "Trichloroacetic acid-induced protein precipitation involves the reversible association of a stable partially structured intermediate" (Rajalingam et al. 2009 Protein Science 18(5), 980–993.) may be relevant.

In the introduction, they mention the conventional explanation is that "TCA forces protein to precipitate by sequestering the protein-bound water" - that is, it may force protein precipitation in a related fashion to chaotropic agents or antichaotropic agents like ammonium sulfate.

Their experiments indicate a more complex explanation. They hypothesize that the negatively charged TCA disrupts electrostatic interactions in the protein, resulting in a partially folded state which is prone to aggregation. The fact that TCA precipitation is less effective for intrinsically disordered proteins lends support to this hypothesis (as they don't have an aggregation-prone partially unfolded state).

The acidic nature of the TCA (the pH effect) helps with the rate of precipitation, but does not appear to be necessary, as the sodium salt of TCA is able to precipitate proteins in neutral solutions, although slower than acidic TCA.

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