title: Insight into the folding inhibition of the HIV-1 protease by a small peptide.
abstract: 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.
authors.affiliation: Computational Science, Department of Chemistry and Applied Biosciences, ETH Zürich, Lugano, Switzerland. massimiliano.bonomi@phys.chem.ethz.ch
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonomi
authors.forename: Francesco L
authors.initials: FL
authors.lastname: Gervasio
authors.forename: Guido
authors.initials: G
authors.lastname: Tiana
authors.forename: Davide
authors.initials: D
authors.lastname: Provasi
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Broglia
authors.forename: Michele
authors.initials: M
authors.lastname: Parrinello
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry* / Q000648:ultrastructure*; D008956:Models, Chemical; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D016333:HIV Protease