Paper Info
Title
Influence of the Membrane Lipophilic Environment on the Structure and on the Substrate Access/Egress Routes of the Human Aromatase Enzyme. A Computational Study.
Abstract
Human aromatase (HA), an enzyme located on the membrane of the endoplasmatic reticulum, is of crucial biological importance in the biosynthesis of estrogens. High levels of estrogens are related with important pathologies, conferring to HA a key role as a pharmacological target. In this study we provide, for the first time, an atomistic model of HA embedded on a membrane model to understand the influence of the membrane lipophilic environment on the structural and dynamical properties of HA and on the access/egress pathways of the substrate (androstenedione, ASD) and of the oxygen molecule (involved in the enzymatic process) into/from the HA active site. To this end we used several computational techniques such as force field-based molecular dynamics (MD) simulations, Random Expulsion MD, Steered MD, and Implicit Ligand Sampling. Our results show that the membrane anchoring does not markedly affect the structural properties and the flexibility of the protein, but they clearly point out that the membrane has a marked effect on the access/egress routes of the reactants, stabilizing the formation of different channels for both ASD and O-2 with respect to those observed in pure water solution. Due to the importance of HA in medicine and since access/egress channels may influence its substrate selectivity, a detailed understanding of the role of the membrane in shaping these channels may be of valuable help in drug design.
Year
DOI
Venue
2012
10.1021/ci300151h
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Field
DocType
Volume
Substrate (chemistry),Aromatase,Enzyme,Biophysics,Biochemistry,Ligand,Combinatorial chemistry,Chemistry,Membrane,Biosynthesis,Molecular dynamics,Active site
Journal
52
Issue
ISSN
Citations 
6
1549-9596
6
PageRank 
References 
Authors
0.61
9
2
Name
Order
Citations
PageRank
Jacopo Sgrignani1123.38
Alessandra Magistrato273.69