Exploring the molecular basis of the enantioselective binding of penicillin G acylase towards a series of 2-aryloxyalkanoic acids: A docking and molecular dynamics study

In the present paper, molecular modeling studies were undertaken in order to shed light on the molecular basis of the observed enantioselectivity of penicillin G acylase (PGA), a well known enzyme for its industrial applications, towards 16 racemic 2-aryloxyalkanoic acids, which have been reported t...

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Bibliographic Details
Published in:Journal of molecular graphics & modelling 2007-03, Vol.25 (6), p.773-783
Main Authors: Lavecchia, Antonio, Cosconati, Sandro, Novellino, Ettore, Calleri, Enrica, Temporini, Caterina, Massolini, Gabriella, Carbonara, Giuseppe, Fracchiolla, Giuseppe, Loiodice, Fulvio
Format: Article
Language:English
Subjects:
Alkanes - chemistry
Arginine - chemistry
Arginine - metabolism
Binding Sites
Binding, Competitive
Carboxylic Acids - chemistry
Carboxylic Acids - metabolism
Computer Simulation
Docking
Enantioselectivity
Models, Molecular
Molecular dynamics
Molecular modeling
Penicillin Amidase - chemistry
Penicillin Amidase - metabolism
Penicillin G acylase
Serine - chemistry
Serine - metabolism
Stereoisomerism
Substrate Specificity
Thermodynamics
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Summary:In the present paper, molecular modeling studies were undertaken in order to shed light on the molecular basis of the observed enantioselectivity of penicillin G acylase (PGA), a well known enzyme for its industrial applications, towards 16 racemic 2-aryloxyalkanoic acids, which have been reported to affect several biological systems. With this intention docking calculations and MD simulations were performed. Docking results indicated that the ( S)-enantiomers establish several electrostatic interactions with SerB1, SerB386 and ArgB263 of PGA. Conversely, the absence of specific polar interactions between the ( R)-enantiomers and ArgB263 seems to be the main reason for the different binding affinities observed between the two enantiomers. Results of molecular dynamics simulations demonstrated that polar interactions are responsible for both the ligand affinity and PGA enantiospecificity. Modeling calculations provided possible explanations for the observed enantioselectivity of the enzyme that rationalize available experimental data and could be the basis for future protein engineering efforts.
ISSN:1093-3263
1873-4243
DOI:10.1016/j.jmgm.2006.07.001