A long-standing goal in evolutionary biology is predicting evolution. Here we show that the architecture of macromolecules fundamentally limits evolutionary predictability. Under physiological conditions, macromolecules, like proteins, flip between multiple structures, forming an ensemble of structures. A mutation affects all of these structures in slightly different ways, redistributing the relative probabilities of structures in the ensemble. As a result, mutations that follow the first mutation have a different effect than they would if introduced before. This implies that knowing the effects of every mutation in an ancestor would be insufficient to predict evolutionary trajectories past the first few steps, leading to profound unpredictability in evolution. We, therefore, conclude that detailed evolutionary predictions are not possible given the chemistry of macromolecules.
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