Low Energy Conformations for Endogenous Mu-Receptor-Specific Peptides
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Low Energy Conformations for Endogenous Mu‑Receptor‑Specific Peptides Bo Lin1 · Robert P. Carty2 · Matthew R. Pincus1 Published online: 25 May 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract We have computed the low energy minima for the two endomorphin peptides, N-acetyl-Tyr-Pro-Trp-Phe-NHCH3 (endomorphin 1) and Tyr-Pro-Phe-Phe-NHCH3 (endomorphin 2) in aqueous solution. These peptides block pain without inducing the harmful side effects of the opiates that bind to the same mu opiate receptor but have short half lives. From over 1000 starting conformations for each peptide, we find less than 200 low energy structures whose conformational energies were ≤ 5 kcal/ mole of the energy of the global minimum. The most probable conformations calculated using the Boltzmann distribution for both peptides were similar to one another. Using the letter representation for backbone conformational states, these most probable structures were D A E E for endomorphin 1 and E A E E for endomorphin 2. Both of these structures form reverse turns at Pro 2-Trp (Phe) 3 resulting in the juxtaposition of the aromatic rings of Tyr 1 and Phe 4. The Trp residue of endomorphin 1 points to the back of the reverse turn. These features may be useful in the design of non-peptide analogues that will have longer half-lives than the peptides. Keywords Endomorphin · Energy minima · Low energy conformations · Most probable conformation · Conformational state · Mu receptor Abbreviations NAc N-Acetyl ECEPP Empirical conformational energies of peptides program DAMGO Modified enkephalin peptide, Tyr-D-Ala-Gly-[S-]-Methyl-Phe-Gly-ol
1 Introduction Treatment of pain often involves the use of opiates, including heroin, morphine, codeine and its derivatives, especially oxycodone, fentanyl and a variety of other drugs. These drugs have the disadvantage that they induce physical * Robert P. Carty [email protected] * Matthew R. Pincus [email protected] 1
Department of Pathology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
Department of Anatomy and Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
2
dependency, addiction and a myriad of other undesirable physical and neuropsychiatric side effects. The mechanism of action of these drugs appears to be their binding to mu receptors, named for the agonist, morphine, in the central nervous system ultimately resulting in decreased nerve conduction in the spinothalamic tract or pain pathway in the central nervous system [1]. These opioids bind with much lower affinities to other receptors involved in pain modulation, i.e., κ, ε, and δ receptors. Naturally occurring peptides have been found to bind to these receptors [1]. Thus, the pentapeptides, Met- and Leuenkephalin (Tyr-Gly-Gly-Phe-Met/Leu) have been found to bind to both ε and δ receptors while the dynorphins bind to κ receptors. Importantly, the enkephalins have been found to bind with high affinities to both mu and ε receptors
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