resumo
We present the first systematic molecular modeling study of the binding properties of murine (mHBP) and human (hHBP) p22HBP protein (heme-binding protein) with four tetrapyrrole ring systems belonging to the heme biosynthetic pathway: iron protoporphyrin IX (HEMIN), protoporphyrin IX (PPIX), coproporphyrin III (CPIII), coproporphyrin I (CPI). The relative binding affinities predicted by our computational study were found to be similar to those observed experimentally, providing a first rational structural analysis of the molecular recognition mechanism, by p22HBP, toward a number of different tetrapyrrole ligands. To probe the structure of these p22HBP protein complexes, docking, molecular dynamics and MM-PBSA methodologies supported by experimental NMR ring current shift data have been employed. The tetrapyrroles studied were found to bind murine p22HBP with the following binding affinity order: HEMIN > PPIX > CPIII > CPI, which ranged from -22.2 to -6.1 kcal/mol. In general, the protein-tetrapyrrole complexes are stabilized by non-bonded interactions between the tetrapyrrole propionate groups and basic residues of the protein, and by the preferential salvation of the complex compared to the unbound components. (C) 2010 Elsevier Inc. All rights reserved.
palavras-chave
MOLECULAR-DYNAMICS; WATER MODELS; FORCE-FIELD; SIMULATION; BACTERIOFERRITIN; IDENTIFICATION; RESTRAINTS; SOLVATION; SOUL/HBP; FAMILY
categoria
Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology
autores
Micaelo, NM; Macedo, AL; Goodfellow, BJ; Felix, V
nossos autores
Brian James Goodfellow
Professor Auxiliar
Vítor Félix
Professor Associado com AgregaçãoGrupos
G5 - Materiais Biomiméticos, Biológicos e Vivos
G6 - Materiais Virtuais e Inteligência Artificial
agradecimentos
The authors acknowledge the Fundacao para a Ciencia e Tecnologia (FCT) for financial support under project PTDC/QUI/64203/2006 with co-participation European Community funds from the FEDER, QREN and COMPET. Nuno M. Micaelo also thanks the FCT for the grant SFRH/BPD/35003/2007.