Protein folding pathways studied by pulsed-and native-state hydrogen exchange

The past three decades have seen the proliferation of studies of the process of protein folding and prediction of protein structures. Despite vast efforts exerted to date, protein folding remains unsolved. This review covers amide hydrogen exchange of proteins, and hydrogen exchange results and the mechanism of protein folding. Under the first topic, focus is on intrinsic exchange rates for ulfolded polypeptides, Linderstrøm-Lang model for amide hydrogen exchange in folded proteins, pulsed-amide H/D exchange method, native-state hydrogen exchange method, and experimental results. For the second topic, discussion addresses the possibility of solving large-scale conformational search problem by discrete folding intermediates, on- and off-pathway nature of folding intermediates, high-resolution structure of a hidden folding intermediate, solving large-scale conformational search problem by a funnel-like energy landscape, cooperativity hypothesis of protein folding, early-folding intermediates in larger proteins, and EX1 hydrogen exchange and protein unfolding.