The physics of protein folding and of non-conventional drug design: Attacking AIDS with its own weapons

General physical principles have taught us that good folders are those sequences of amino acids which have a particularly low energy in the native state. Furthermore, it has become clear during the last few years that most of the stabilization energy in this state is associated with few, strongly interacting, highly conserved, as a rule hydrophobic (hot) amino acids, amino acids which in the very early stages of the folding process stabilize local elementary structures (LES). The docking of these LES gives rise to the (post-critical) folding nucleus (FN), that is the minimum set of native contacts needed to bring the system over the highest free-energy barrier of the whole folding process. This physical scenario of the folding of proteins contains the clue for designing protein-folding inhibitors. A particularly attractive example of the workings of such non-conventional drugs is provided by the folding inhibitors of the HIV-1 Protease. Because HIV-1-PR is an essential enzyme in the viral life cycle, inhibition of the protease can control AIDS. In this paper we will review the theoretical and experimental evidence which testifies to the second-order phase transition undergone by the evolution of chains of amino acids from a random sequence to a good folder, and to the hierarchical physical mechanism which is at the basis of the first-order phase transition undergone by the enzyme (good folder): from the unfolded to the native, biologically active state of the protein. Special emphasis of this review will be set on the identification of hot, warm and cold sites as well as of the LES, and of (post-critical) folding nucleus (FN) of the enzyme. This identification will then be used to individuate the best candidates of folding inhibitors, that is peptides (p-LES) which, displaying the same sequence of LES, attach to the complementary LES, and denaturate the enzyme. Because LES have been designed by evolution over myriad of generations, p-LES are expected to be efficient inhibitors unlike to create resistance.