Docking and molecular dynamics simulation studies on glycation-induced conformational changes of human paraoxonase 1.
Eur Biophys J
; 41(2): 241-8, 2012 Feb.
Article
em En
| MEDLINE
| ID: mdl-22193970
ABSTRACT
Human paraoxonase 1 (huPON1) is a calcium-dependent esterase responsible for hydrolysis of a wide variety of substrates including organophosphates, esters, lactones, and paraoxon. Although its natural substrate is unknown, the action of PON as an antioxidant is well documented. Because recent reports have suggested glycation may induce reduced PON activity in diabetes, we investigated the structural features of huPON1 and its glycated mutant by template-based modeling, docking, and molecular dynamics (MD) simulations. Our results corroborated the importance of the His115-His134 dyad in both the lactonase and paraoxonase activity of huPON1. Structural alterations in the glycated model reflected weak interactions between the docked substrate and the active site cleft. We also used MD simulation to gain insight into glycation-induced conformational changes of huPON1 and the implication of this on depleted enzymatic activity. The catalytic calcium found on the surface interacts with the side chain oxygen of residues, including Asn224, Asn270, Asn168, Asp269, and Glu53, and this interaction with the respective residues undergoes minor displacement on glycation. The root-mean-square fluctuation had high motional flexibility in the non-glycated model whereas the conformation of the glycated structure was comparatively stable. Our findings emphasize the consequence of glycation-induced alterations and their effect on overall enzymatic activity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Domínio Catalítico
/
Arildialquilfosfatase
/
Simulação de Dinâmica Molecular
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article