Protein folding: Vexing debates on a fundamental problem

•Several debates are flourishing in the protein folding field.•Compaction of the denatured state measured by single molecule techniques is challenged by SAXS.•The presence of nucleation sites probed by Φ analysis is constantly being criticised.•Long transition path times challenge molecular dynamics simulations.

The folding of proteins has been at the heart of protein chemistry and biophysics ever since the pioneering experiments by the labs of Fred Richards and Christian Anfinsen. But, despite nearly 60 years of intense research, there are unresolved issues and a lively debate regarding some aspects of this fundamental problem. In this review we give a personal account on some key topics in the field: (i) the nature of the denatured state of a protein, (ii) nucleation sites in the folding reaction, and (iii) the time it takes for individual molecules to traverse the transition state.

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