title: Molecular dynamics simulations of the free and inhibitor-bound cruzain systems in aqueous solvent: insights on the inhibition mechanism in acidic pH.
abstract: The major cysteine protease of Trypanosoma cruzi, cruzain (CRZ), has been described as a therapeutic target for Chagas' disease, which affects millions of people worldwide. Thus, a series of CRZ inhibitors has been studied, including a new competitive inhibitor, Nequimed176 (NEQ176). Nevertheless, the structural and dynamic basis for CRZ inhibition remains unclear. Hoping to contribute to this ever-growing understanding of timescale dynamics in the CRZ inhibition mechanism, we have performed the first study using 100 ns of molecular dynamics (MD) simulations of two CRZ systems in an aqueous solvent under pH 5.5: CRZ in the apo form (ligand free) and CRZ complexed to NEQ176. According to the MD simulations, the enzyme adopts an open conformation in the apo form and a closed conformation in the NEQ176-CRZ complex. We also suggest that this closed conformation is related to the hydrogen-bonding interactions between NEQ176 and CRZ, which occurs through key residues, mainly Gly66, Met68, Asn69, and Leu160. In addition, the cross-correlation analysis shows evidence of the correlated motions among Ala110-Asp140, Leu160-Gly189, and Glu190-Gly215 subdomains, as well as, the movements related to Ala1-Thr59 and Asp60-Pro90 regions seem to be crucial for CRZ activity.
authors.affiliation: a Laboratório de Química Medicinal, Faculdade de Farmácia , Universidade Federal Fluminense (UFF) , Rua Mário Viana 523, Santa Rosa , Niterói , RJ 24241-000 , Brazil.
authors.forename: L V B
authors.initials: LV
authors.lastname: Hoelz
authors.affiliation: a Laboratório de Química Medicinal, Faculdade de Farmácia , Universidade Federal Fluminense (UFF) , Rua Mário Viana 523, Santa Rosa , Niterói , RJ 24241-000 , Brazil.
authors.forename: V F
authors.initials: VF
authors.lastname: Leal
authors.affiliation: b Laboratório ModMolQSAR, Faculdade de Farmácia , Universidade Federal do Rio de Janeiro (UFRJ) , Av. Carlos Chagas Filho 373, CCS, Rio de Janeiro , RJ 21941-599 , Brazil.
authors.forename: C R
authors.initials: CR
authors.lastname: Rodrigues
authors.affiliation: c Laboratório de Modelagem e Dinâmica Molecular , Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ) , Av. Carlos Chagas Filho 373, CCS, Rio de Janeiro , RJ 21941-902 , Brazil.
authors.forename: P G
authors.initials: PG
authors.lastname: Pascutti
authors.affiliation: d Laboratório de Modelagem Molecular , Instituto de Química, Universidade Federal do Rio de Janeiro (UFRJ) , Av. Athos da Silveira Ramos 149, CT, Rio de Janeiro , RJ 21949-900 , Brazil.
authors.forename: M G
authors.initials: MG
authors.lastname: Albuquerque
authors.affiliation: a Laboratório de Química Medicinal, Faculdade de Farmácia , Universidade Federal Fluminense (UFF) , Rua Mário Viana 523, Santa Rosa , Niterói , RJ 24241-000 , Brazil.
authors.forename: E M F
authors.initials: EM
authors.lastname: Muri
authors.affiliation: a Laboratório de Química Medicinal, Faculdade de Farmácia , Universidade Federal Fluminense (UFF) , Rua Mário Viana 523, Santa Rosa , Niterói , RJ 24241-000 , Brazil.
authors.forename: L R S
authors.initials: LR
authors.lastname: Dias
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D054730:Protein Interaction Domains and Motifs; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D012997:Solvents; D003546:Cysteine Endopeptidases
keywords: Chagas’ disease; Nequimed176; cruzain; cysteine protease inhibitors; molecular dynamics simulation