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 (S2) and 83-93 (S8) 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-S8, 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-S8 is robust. On the other hand, there is no direct evidence demonstrating the validity of the proposed mechanism of inhibition associated with p-S8. To shed light on this question and to provide the basis for the design of a molecule mimetic to p-S8, 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-S2 and p-S8; b), the details of the docking mechanism of the two peptides and the free energy associated with this process. Whereas p-S8 is found to be well structured, p-S2 is rather flexible, wrapping itself around p-S8 to give rise to the FN, which is stabilized by three particular hydrogen bonds.