THE EUROPEAN PHYSICAL JOURNAL SPECIAL TOPICS Regular Article

Abstract. It is commonly accepted that water plays an essential role in determining both the stability of the 3D structure of protein, as well as speed of the protein folding process. How exactly water does that, is still very controversial. Until recently it was believed that various hydrophobic effects, which originate from the solvent, are the domi-nant factors. In the first part of this article we discuss the paradigm shift from hydrophobic (HφO), to a hydrophilic (HφI) based theory of protein folding. Next, we analyze the types of solvent-induced forces that are exerted on various groups on the protein. We find that the HφI–HφI solvent-induced forces are likely to be the strongest. These forces originate from water molecules forming hydrogen-bonded-bridges between two, or more hydrophilic groups attached to the protein. Therefore, it is argued that these forces are also the forces that force the protein to fold, in a short time, along a narrow range of pathways. This paradigm shift brings us, as close as we can hope for, to a solution to the general problem of protein folding.