Tetrapyrrole binding affinity of the murine and human p22HBP heme-binding proteins

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 solvation of the complex compared to the unbound components.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (171 K)Download as PowerPoint slideResearch highlights▶ Human and murine HBP bind HEMIN, PPIX and tetrapyrrole biosynthetic intermediates. ▶ Experimental and theoretical relative binding affinities have the same order. ▶ Tetrapyrrole molecules are recognized by HBP via multiple non-bonded interactions.