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In Silico Analysis of Homologous Heterodimers of Cruzipain-Chagasin from Structural Models Built by Homology.

ABSTRACT: The present study gives an overview of the binding energetics of the homologous heterodimers of cruzipain-chagasin based on the binding energy (?Gb) prediction obtained with FoldX. This analysis involves a total of 70 homologous models of the cruzipain-chagasin complex which were constructed by homology from the combinatory variation of nine papain-like cysteine peptidase structures and seven cysteine protease inhibitor structures (as chagasin-like and cystatin-like inhibitors). Only 32 systems have been evaluated experimentally, ?Gbexperimental values previously reported. Therefore, the result of the multiple analysis in terms of the thermodynamic parameters, are shown as relative energy |??G| = |?Gbfrom FoldX - ?Gbexperimental|. Nine models were identified that recorded |??G| < 1.3, five models to 2.8 > |??G| > 1.3 and the other 18 models, values of |??G| > 2.8. The energetic analysis of the contribution of ?H and ?S to ?Gb to the 14-molecular model presents a ?Gb mostly ?H-driven at neutral pH and at an ionic strength (I) of 0.15 M. The dependence of ?Gb(I,pH) at 298 K to the cruzipain-chagasin complex predicts a linear dependence of ?Gb(I). The computational protocol allowed the identification and prediction of thermodynamics binding energy parameters for cruzipain-chagasin-like heterodimers.

SUBMITTER: Reyes-Espinosa F

PROVIDER: S-EPMC6470822 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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In Silico Analysis of Homologous Heterodimers of Cruzipain-Chagasin from Structural Models Built by Homology.

Reyes-Espinosa Francisco F Juárez-Saldivar Alfredo A Palos Isidro I Herrera-Mayorga Verónica V García-Pérez Carlos C Rivera Gildardo G

International journal of molecular sciences 20190315 6

The present study gives an overview of the binding energetics of the homologous heterodimers of cruzipain-chagasin based on the binding energy (Δ<i>G</i><sub>b</sub>) prediction obtained with FoldX. This analysis involves a total of 70 homologous models of the cruzipain-chagasin complex which were constructed by homology from the combinatory variation of nine papain-like cysteine peptidase structures and seven cysteine protease inhibitor structures (as chagasin-like and cystatin-like inhibitors) ...[more]

PMID: 30875920

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Project description:Trypanosoma cruzi, the agent of Chagas disease, is a complex of genetically diverse isolates highly phylogenetically related to T. cruzi-like species, Trypanosoma cruzi marinkellei and Trypanosoma dionisii, all sharing morphology of blood and culture forms and development within cells. However, they differ in hosts, vectors and pathogenicity: T. cruzi is a human pathogen infective to virtually all mammals whilst the other two species are non-pathogenic and bat restricted. Previous studies suggest that variations in expression levels and genetic diversity of cruzipain, the major isoform of cathepsin L-like (CATL) enzymes of T. cruzi, correlate with levels of cellular invasion, differentiation, virulence and pathogenicity of distinct strains. In this study, we compared 80 sequences of genes encoding cruzipain from 25 T. cruzi isolates representative of all discrete typing units (DTUs TcI-TcVI) and the new genotype Tcbat and 10 sequences of homologous genes from other species. The catalytic domain repertoires diverged according to DTUs and trypanosome species. Relatively homogeneous sequences are found within and among isolates of the same DTU except TcV and TcVI, which displayed sequences unique or identical to those of TcII and TcIII, supporting their origin from the hybridization between these two DTUs. In network genealogies, sequences from T. cruzi clustered tightly together and closer to T. c. marinkellei than to T. dionisii and largely differed from homologues of T. rangeli and T. b. brucei. Here, analysis of isolates representative of the overall biological and genetic diversity of T. cruzi and closest T. cruzi-like species evidenced DTU- and species-specific polymorphisms corroborating phylogenetic relationships inferred with other genes. Comparison of both phylogenetically close and distant trypanosomes is valuable to understand host-parasite interactions, virulence and pathogenicity. Our findings corroborate cruzipain as valuable target for drugs, vaccine, diagnostic and genotyping approaches.

Dataset Information

In Silico Analysis of Homologous Heterodimers of Cruzipain-Chagasin from Structural Models Built by Homology.

Publications

In Silico Analysis of Homologous Heterodimers of Cruzipain-Chagasin from Structural Models Built by Homology.

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