title: Exploring the unbinding of Leishmania (L.) amazonensis CPB derived-epitopes from H2 MHC class I proteins.
abstract: New strategies to control Leishmania disease demand an extensive knowledge about several aspects of infection including the understanding of its molecular events. In murine models, cysteine proteinase B from Leishmania amazonensis promotes regulation of immune response, and fragments from its C-terminus extension (cyspep) can play a decisive role in the host-parasite interaction. The interaction between cyspep-derived peptides and major histocompatibility complex (MHC) proteins is a crucial factor in Leishmania infections. Seven cyspep-derived peptides, previously identified as capable of interacting with H-2 (murine) MHC class I proteins, were studied in this work. We established a protocol to simulate the unbinding of these peptides from the cleft of H-2 receptors. From the simulations, we estimated the corresponding free energy of dissociation (ΔGd ) and described the molecular events that occur during the exit of peptides from the cleft. To test the reliability of this method, we first applied it to a calibration set of four crystallographic MHC/peptide complexes. Next, we explored the unbinding of the seven complexes mentioned above. Results were consistent with ΔGd values obtained from surface plasmon resonance (SPR) experiments. We also identified some of the primary interactions between peptides and H-2 receptors, and we detected three regions of influence for the interaction. This pattern was systematically observed for the peptides and helped determine a minimum distance for the real interaction between peptides and H-2 proteins occurring at ∼ 25 Å.
authors.affiliation: Programa De Computação Científica (PROCC), Fundação Oswaldo Cruz, Manguinhos, Rio De Janeiro, RJ, CEP 21040-360, Brazil.|Faculdade De Educação Tecnológica Do Estado Do Rio De Janeiro (FAETERJ), Rio De Janeiro, RJ, CEP 21311-280, Brazil.
authors.forename: Artur M L
authors.initials: AM
authors.lastname: Brandt
authors.affiliation: Programa De Computação Científica (PROCC), Fundação Oswaldo Cruz, Manguinhos, Rio De Janeiro, RJ, CEP 21040-360, Brazil.
authors.forename: Paulo Ricardo
authors.initials: PR
authors.lastname: Batista
authors.affiliation: Laboratório De Biologia Molecular E Doenças Endêmicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio De Janeiro, RJ, CEP 21040-360, Brazil.
authors.forename: Franklin
authors.initials: F
authors.lastname: Souza-Silva
authors.affiliation: Laboratório De Biologia Molecular E Doenças Endêmicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio De Janeiro, RJ, CEP 21040-360, Brazil.
authors.forename: Carlos Roberto
authors.initials: CR
authors.lastname: Alves
authors.affiliation: Programa De Computação Científica (PROCC), Fundação Oswaldo Cruz, Manguinhos, Rio De Janeiro, RJ, CEP 21040-360, Brazil.
authors.forename: Ernesto Raul
authors.initials: ER
authors.lastname: Caffarena
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D057056:Cysteine Proteases / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D007892:Leishmania braziliensis / Q000737:chemistry* / Q000472:pathogenicity; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000469:parasitology; D051379:Mice; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D015800:Protozoan Proteins; D057056:Cysteine Proteases
keywords: H-2 Db, H-2 Kd, H-2 Kk and H-2 Ld haplotypes; Leishmania (Leishmania) amazonensis; free energy surface; immunological epitopes; metadynamics