Downhill dynamics and the molecular rate of protein folding

Proteins are held together by many weak contacts, each corresponding to a local reaction coordinate. The activation barrier for folding is distributed along a resultant global folding coordinate. Hence folding barriers are low, and could even become comparable to the thermal energy kT. In that case, proteins become downhill folders, with folding times in the microsecond region. Small barriers allow the diffusion of population along the reaction coordinate – the molecular rate – to be observed directly. Five simple free energy building blocks can explain all experimentally observed fast folding data, revealing a range of behaviors from low barrier crossings to completely downhill folding.