The probability distribution of side‐chain conformations in [Leu] and [Met]enkephalin determines the potency and selectivity to μ and δ opiate receptors

Abstract

The structure of enkephalin, a small neuropeptide with five amino acids, has been simulated on computers using molecular dynamics. Such simulations exhibit a few stable conformations, which also have been identified experimentally. The simulations provide the possibility to perform cluster analysis in the space defined by potentially pharmacophoric measures such as dihedral angles, side-chain orientation, etc. By analyzing the statistics of the resulting clusters, the probability distribution of the side-chain conformations may be determined. These probabilities allow us to predict the selectivity of [Leu]enkephalin and [Met]enkephalin to the known mu- and delta-type opiate receptors to which they bind as agonists. Other plausible consequences of these probability distributions are discussed in relation to the way in which they may influence the dynamics of the synapse.

Conformational Heterogeneity of a Leucine Enkephalin Analogue in Aqueous Solution and Sodium Dodecyl Sulfate Micelles: Comparison of Time-Resolved FRET and Molecular Dynamics Simulations

“…9.5 Å, and 13.4 Å. This distance distribution compares favorably with the distribution of Tyr-Phe distances predicted in a 10-ns MD simulation of YGGFL,12 suggesting that the conformational distributions for YGGWL and YGGFL are similar. It is not clear whether minor differences between the distributions (e.g.…”

“…In addition, it permits comparison to simulations of Leu-enkephalin (YGGFL). In a 10-ns simulation12 with the TIP3P water model, YGGFL sampled a range of Tyr-to-Phe distances from 5 to 15 Å, similar to the Tyr-to-Trp distances obtained in the simulation presented here. The distribution of Tyr-to-Phe distances in the 10-ns simulation formed three well defined populations with ring–to-ring distances of 6 to 8 Å, 9 to 12 Å, and 12 to 15 Å.…”

“…The average distance between the pharmacore groups (Tyr and Phe) may correlate with selectivity toward different opioid receptors 20. Computational studies of enkephalin structure support this hypothesis 12. The δ-opioid receptor may be sensitive to a wide range of conformations with aromatic separations of 5 to 15 Å 12,20.…”

Parabolic section and distance excess of space curves applied to protein structure classification

“…The distance excess given by the end-to-end distance minus the length of the backbone curve, is thus essentially given by the end-to-end distance of the protein. For one very short protein, which then is called a peptide, the end-to-end distance has successfully been used as a structural descriptor [14]. However, for structural classification of longer proteins, the end-to-end distance is not expected to perform well for two reasons: The ends of a protein are often flexible, and secondly, when cutting large proteins into domains, then the end-to-end distance of a domain depends strongly on the decision on where to cut the protein into domains.…”

Use of vibrational spectroscopy to study protein and DNA structure, hydration, and binding of biomolecules: A combined theoretical and experimental approach

“…In the study published the energy levels and quantum states of Leu‐enkephalin conformations were investigated both theoretically and experimentally both with quantum and classical mechanical methods 87. Also functional studies were made where the probability distribution of side‐chain conformations in Met‐ and Leu‐enkephalin turned out to determine the potency and selectivity to mu‐ and delta‐opiate receptors 88.…”