Ubiquitin folds via a flip-twist-lock mechanism

To perform specific functional activities, the majority of proteins should fold into their distinct three-dimensional conformations. However, the biologically active conformation of a protein is generally found to be marginally stable than the other conformations that the chain can adopt. How a protein finds its native conformation from its post-synthesis unfolded structure in a complex conformational landscape is the unsolved question that still drives the protein folding community. Here, we report the folding mechanism of a globular protein, ubiquitin, from its chemically denatured state using all-atom molecular dynamics simulations. From the kinetic analysis of the simulated trajectories we show that the folding process can be described by the hydrophobic collapse mechanism, initiated by the "dewetting transition", and subsequently assisted by the origination of an N-terminal folding nucleus, and finally supported by a native salt-bridge interaction between K11 and E34. We show that ubiquitin folds via an intermediate. Finally, we confirm the presence of "biological water" and explain its role to the folding process.