This article reviews the evolution of the “dominant forces” in protein folding theory. The review starts with the idea that hydrogen bonds (HB) were believed to be the dominate factors in the stability of proteins. This paradigm suffered a devastating blow in 1955. Following Schellman’s experiments on the association of urea in aqueous solutions, it was concluded that HB could not contribute significantly to the stability of proteins. This conclusion was later formulated as the ‘HB-inventory argument’, which stated that hydrogen bonding with water molecules compete with intramolecular hydrogen-bonds. As a result, the HB paradigm fell from grace. The void created was immediately filled by Kauzmann’s idea of the hydrophobic (HΦO) effect, which reigned supreme in biochemical literatures for over 50 years. In the past twenty years, the dominance of the HΦO effects was seriously contested. Cracks in the HB-inventory argument on one hand, and doubts about the adequacy of Kauzmann’s model for the HΦO effect, on the other hand, have led to a comeback of the HBs, along with a host of new hydrophilic (HΦI) effects. The HΦO effects lost much of its power - which it never really had - in explaining protein folding and protein-protein association. Instead, the more powerful and richer repertoire of HΦI effects took over the reins. The HΦI interactions offered simple and straightforward answers to the problem of protein stability. The HΦI forces also offered an explanation of the fast process of protein folding.
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