Insight into the Folding Inhibition of the HIV-1 Protease by a Small Peptide

It has recently been shown that the highly protected segments 24–34 (S(2)) and 83–93 (S(8)) of each of the two 99-mers of human immunodeficiency virus type 1 protease play an essential role in the folding of the monomers, giving rise to the so-called (postcritical) folding nucleus ((FN) minimum condensation unit ensuring folding) when they dock. This scenario received further support from model calculations that demonstrated that the peptide p-S(8), displaying an amino acid sequence identical to the corresponding (83–93) segment of the monomer, can be used to interfere with the formation of the FN and eventually to inhibit folding by docking the fragment 24–34. Experiments in vitro and in cells infected with ex vivo wild-type and multiresistant HIV isolates confirm that the inhibition power of p-S(8) is robust. On the other hand, there is no direct evidence demonstrating the validity of the proposed mechanism of inhibition associated with p-S(8). To shed light on this question and to provide the basis for the design of a molecule mimetic to p-S(8), to be used as lead of an eventual drug against AIDS, we study, in this paper, with the help of all-atom simulations in explicit solvent and the novel method of metadynamics combined with parallel tempering: a), the free energy and the equilibrium structure of each of the peptides p-S(2) and p-S(8); b), the details of the docking mechanism of the two peptides and the free energy associated with this process. Whereas p-S(8) is found to be well structured, p-S(2) is rather flexible, wrapping itself around p-S(8) to give rise to the FN, which is stabilized by three particular hydrogen bonds.