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Earlier studies have reported that trimethylamine N-oxide (TMAO), a naturally occurring osmolyte, is a universal stabilizer of proteins because it folds unstructured proteins and counteracts the deleterious effects of urea and salts on the structure and function of proteins. This conclusion has been reached from the studies of the effect of TMAO on proteins in the pH range 6.0–8.0. In this pH range TMAO is almost neutral (zwitterionic form), for it has a pK_a of 4.66 ± 0.10. We have asked the question of whether the effect of TMAO on protein stability is pH-dependent. To answer this question we have carried out thermal denaturation studies of lysozyme, ribonuclease-A, and apo-α-lactalbumin in the presence of various TMAO concentrations at different pH values above and below the pK_a of TMAO. The main conclusion of this study is that near room temperature TMAO destabilizes proteins at pH values below its pK_a …