Protein folding success depends on the direction and speed of polypeptide chain appearance

The failure of proteins to fold correctly to their native, functional structures is the molecular basis of many human diseases. Every protein is introduced to the cellular environment from N-to C-terminus as it is synthesized, which can enable the N-terminus to begin folding before the C-terminus appears. Here we show that direction and speed of appearance alone can significantly affect whether a protein will fold to its native structure, versus misfold. This sensitivity demonstrates that folding energy landscapes are sufficiently rugged that conformations adopted by the first portion of the protein to appear can significantly impact subsequent folding steps. Despite high structural similarity, homologous proteins had different sensitivities to vectorial appearance, indicating the native topology is insufficient to determine contours of the energy landscape.