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Heterodimerization of the Entamoeba histolytica EhCPADH virulence complex through molecular dynamics and protein-protein docking
- Source :
- Journal of biomolecular structuredynamics. 35(3)
- Publication Year :
- 2016
-
Abstract
- EhCPADH is a protein complex involved in the virulence of Entamoeba histolytica, the protozoan responsible for human amebiasis. It is formed by the EhCP112 cysteine protease and the EhADH adhesin. To explore the molecular basis of the complex formation, three-dimensional models were built for both proteins and molecular dynamics simulations (MDS) and docking calculations were performed. Results predicted that the pEhCP112 proenzyme and the mEhCP112 mature enzyme were globular and peripheral membrane proteins. Interestingly, in pEhCP112, the propeptide appeared hiding the catalytic site (C167, H329, N348); while in mEhCP112, this site was exposed and its residues were found structurally closer than in pEhCP112. EhADH emerged as an extended peripheral membrane protein with high fluctuation in Bro1 and V shape domains. 500 ns-long MDS and protein-protein docking predictions evidenced different heterodimeric complexes with the lowest free energy. pEhCP112 interacted with EhADH by the propeptide and C-terminal regions and mEhCP112 by the C-terminal through hydrogen bonds. In contrast, EhADH bound to mEhCP112 by 442-479 residues, adjacent to the target cell-adherence region (480-600 residues), and by the Bro1 domain (9-349 residues). Calculations of the effective binding free energy and per residue free energy decomposition showed that EhADH binds to mEhCP112 with a higher binding energy than to pEhCP112, mainly through van der Waals interactions and the nonpolar part of solvation energy. The EhADH and EhCP112 structural relationship was validated in trophozoites by immunofluorescence, TEM, and immunoprecipitation assays. Experimental findings fair agreed with in silico results.
- Subjects :
- 0301 basic medicine
Immunoprecipitation
Protein Conformation
Protozoan Proteins
Plasma protein binding
Molecular Dynamics Simulation
Bioinformatics
Molecular Docking Simulation
03 medical and health sciences
Entamoeba histolytica
Protein structure
Structural Biology
Humans
Protein Interaction Domains and Motifs
Molecular Biology
030102 biochemistry & molecular biology
biology
Peripheral membrane protein
Alcohol Dehydrogenase
Membrane Proteins
General Medicine
biology.organism_classification
030104 developmental biology
Biochemistry
Membrane protein
Docking (molecular)
Protein Multimerization
Protein Binding
Subjects
Details
- ISSN :
- 15380254
- Volume :
- 35
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of biomolecular structuredynamics
- Accession number :
- edsair.doi.dedup.....d58ce3ac0d312a27e0530291890a2815