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Three‐dimensional model of the human aromatase enzyme and density functional parameterization of the iron‐containing protoporphyrin IX for a molecular dynamics study of heme‐cysteinato cytochromes
Author(s) -
Favia Angelo Danilo,
Cavalli Andrea,
Masetti Matteo,
Carotti Angelo,
Recanatini Maurizio
Publication year - 2006
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20829
Subject(s) - aromatase , molecular dynamics , homology modeling , chemistry , cytochrome p450 , heme , enzyme , molecular model , protoporphyrin ix , density functional theory , active site , computational chemistry , stereochemistry , computational biology , biochemistry , biology , genetics , organic chemistry , breast cancer , photodynamic therapy , cancer
Mammalian cytochromes P450 (CYP) are enzymes of great biological and pharmaco‐toxicological relevance. Due to their membrane‐bound nature, the structural characterization of these proteins is extremely difficult, and therefore computational techniques, such as comparative modeling, may help obtaining reliable structures of members of this family. An important feature of CYP is the presence of an iron‐containing porphyrin group at the enzyme active site. This calls for quantum chemical calculations to derive charges and parameters suitable for classical force field‐based investigations of this proteins family. In this report, we first carried out density functional theory (DFT) computations to derive suitable charges for the Fe 2+ ‐containing heme group of P450 enzymes. Then, by means of the homology modeling technique, and taking advantage of the recently published crystal structure of the human CYP2C9, we built a new model of the human aromatase (CYP19) enzyme. Furthermore, to study the thermal stability of the new model as well as to test the suitability of the new DFT‐based heme parameters, molecular dynamics (MD) simulations were carried out on both CYP2C9 and CYP19. Finally, the last few ns of aromatase MD trajectories were investigated following the essential dynamics protocol that allowed the detection of some correlated motions among some protein domains. Proteins 2006. © 2006 Wiley‐Liss, Inc.