Abstract
Hemorphins are atypical endogenous opioid peptides produced by the cleavage of hemoglobin beta chain. Several studies have reported the therapeutic potential of hemorphin in memory enhancement, blood regulation, and analgesia. However, the mode of interaction of hemorphin with its target remains largely elusive. The decapeptide LVV-hemorphin-7 is the most stable form of hemorphin. It binds with high affinity to mu-opioid receptors (MOR), angiotensin-converting enzyme (ACE) and insulin-regulated aminopeptidase (IRAP). In this study, computational methods were used extensively to elucidate the most likely binding pose of mammalian LVV-hemorphin-7 with the aforementioned proteins and to calculate the binding affinity. Additionally, alignment of mammalian hemorphin sequences showed that the hemorphin sequence of the camel harbors a variation – a Q > R substitution at position 8. This study also investigated the binding affinity and the interaction mechanism of camel LVV-hemorphin-7 with these proteins. To gain a better understanding of the dynamics of the molecular interactions between the selected targets and hemorphin peptides, 100 ns molecular dynamics simulations of the best-ranked poses were performed. Simulations highlighted major interactions between the peptides and key residues in the binding site of the proteins. Interestingly, camel hemorphin had a higher binding affinity and showed more interactions with all three proteins when compared to the canonical mammalian LVV-hemorphin-7. Thus, camel LVV-hemorphin-7 could be explored as a potent therapeutic agent for memory loss, hypertension, and analgesia.
Highlights
Initial efforts in the 1980s to recognize endogenously produced opioid peptides led to the characterization of hemoglobin-derived (Hb-derived) peptides that have opiate-like activity[1]
Chimpanzee, camel, pig, and rabbit it lies between amino acid positions 32 to 41 in the Hemoglobin beta (HBB) protein sequence
Hydrophobic interactions were formed between camel LVV-hemorphin-7 and Tyr[328], which is consistent with a previous report that indicated that hemorphin interacts with Tyr[326] of mouse MOR49,51,56
Summary
Initial efforts in the 1980s to recognize endogenously produced opioid peptides led to the characterization of hemoglobin-derived (Hb-derived) peptides that have opiate-like activity[1] These peptides are short, 4–10 amino acids in length and are released during physiological or physiopathological hemoglobin beta-chain proteolytic degradation[2]. RAS originated from the classical renin/angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/ angiotensin II type I (AT1) receptor axis and has a physiological role in the regulation of cardiovascular and renal function, aldosterone biosynthesis and release, blood pressure and body salt, and fluid balance[27]. LVV-hemorphin-7 was identified as an endogenous high-affinity ligand of the presumed angiotensin IV receptor (AT4R)[19] Further characterization of this putative receptor suggested that the protein was analogous to IRAP, a type II integral membrane protein whose catalytic activity is inhibited by LVV-hemorphin-7 and Ang IV35–37. In vivo microdialysis revealed that LVV-hemorphin-7 enhanced spatial working memory without a significant increase in blood flow or hippocampal glucose uptake[41]
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