abstract
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.
keywords
MOLECULAR-DYNAMICS; WATER MODELS; FORCE-FIELD; SIMULATION; BACTERIOFERRITIN; IDENTIFICATION; RESTRAINTS; SOLVATION; SOUL/HBP; FAMILY
subject category
Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology
authors
Micaelo, NM; Macedo, AL; Goodfellow, BJ; Felix, V
our authors
Brian James Goodfellow
Assistant Professor
Vítor Félix
Associate Professor with AggregationGroups
G5 - Biomimetic, Biological and Living Materials
G6 - Virtual Materials and Artificial Intelligence
acknowledgements
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.