Structural Insights into σ1 Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations
Abstract
:1. Introduction
- (i)
- Carrying out independent MD simulations for the top-ranked poses of each ligand;
- (ii)
- Examining the frequency of contacts and patterns between different ligand moieties and the receptor; ligand and different receptor residues; maps of different ligand moieties vs. different receptor residues;
- (ii)
- Determining the binding energies (ΔGbind) and decomposing them according to the molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) approach to identify the most important contributions from polar and nonpolar contacts. Decomposition of ΔGbind refers to terms such as ionic bond (or salt bridge) and hydrogen bond where the latter contains also attractive van der Waals and hydrophobic interactions essential for stabilizing the structure;
- (iv)
- Searching for a relationship/trend between ΔGbind and hydrophobicity/hydrophilicity of the residues through the linear regressions based on the studied ligands being treated as a training set.
2. Method
2.1. Ligand Preparation
2.2. Receptor Preparation
2.3. Molecular Docking of Ligands to the σ1 Receptor
2.4. Molecular Dynamics Simulation of the Receptor–Ligand Complex
2.5. The Formal Analysis of the MD Simulations and Presentation
2.6. MM/PBSA Calculations for Binding Free Energy
2.7. Simulation of the PD144418 Ligand
3. Results and Discussions
3.1. Dynamical Properties of the σ1 Receptor–Ligand Interactions
- (i)
- The first group is localized around Asp126 and forms the intermolecular salt bridge between the protonated nitrogen atom (N-H+) in the ligands and the carboxyl (COO−) group of the receptor Glu172 residue. We include also the stable hydrogen bonds between the carboxyl C=O group of Thr181 with the OH groups of the ligands in this region.
- (ii)
- The second region is placed around the Tyr103 residue and plays a determining role in the π-π stacking interactions between Tyr103 and the aromatic/heteroaromatic rings of FENT, HALO, MORPH, PTZ, and PHZ.
- (iii)
- It is noticeable that the residues (Phe107, Trp164, Ile178, Val162, Leu105, Leu182, and Ala185) from the third group belong to the hydrophobic pocket. They yield the required van der Waals and hydrophobic interactions, arranging appropriately the hydrophobic moieties of the ligands.
3.2. Ligand–Receptor Binding in Terms of the Frequency of Ligand–Receptor Contacts
- (i)
- the ligand moieties with the receptor;
- (ii)
- the receptor residues with the whole ligand;
- (iii)
- the ligand–residue contact maps averaged over the MD trajectory.
3.3. The Binding Energy Analysis
- (A)
- Hence, the highest total binding energy is found for FENT, while the smallest is for S-PTZ. Moreover, even if the errors are taken into account and one considers only the low limits, the above conclusions remain true.
- (B)
- On the other hand, the values of total interaction energies of the most strongly interacting ligands—FENT, HALO, R-PHZ, and S-PHZ—are within the error bars of each other. The same holds true for the most weakly interacting ligands—S-PTZ, R-PTZ, and MORPH—for which the total interaction energies are also within the error bars of each other.
- (C)
- The high result for FENT is supported by both the highest electrostatic term and one of the highest van der Waals. FENT exhibits the largest attractive contribution and despite the fact that the repulsive term for it is also one of the two largest, the difference is still the biggest.
- (i)
- (ii)
- (iii)
- On the other hand, the HALO ligand, which is the strongest σ1 receptor antagonist considered here (Ki = 0.65 nM [13]) exhibits the second highest number of contacts and the attractive energy term.
- (iv)
- Unfortunately, the computational predictions of the FENT binding energy were not successful. For fentanyl, the experimental Ki was estimated to be greater than 1000 nM [48,49], whereas in our calculations both the number of contacts and energy terms indicate FENT to interact very strongly (Figure 5b).
- (v)
- The other studied ligands, R-PHZ, R-PTZ and S-PTZ, are located somewhere between the extreme interactions. However, they fit the predicted tendencies (Figure 5b).
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are not available from the authors. |
Ligand ∆E | FENT | HALO | MORPH | R-PTZ | S-PTZ | R-PHZ | S-PHZ |
---|---|---|---|---|---|---|---|
ΔEtot | −345 (35) | −320 (20) | −290 (20) | −275 (20) | −250 (25) | −320 (25) | −305 (25) |
ΔEvdW | −175 (20) | −185 (15) | −150 (15) | −145 (15) | −145 (15) | −145 (15) | −165 (15) |
ΔEelect | −610 (40) | −545 (20) | −475 (20) | −485 (25) | −490 (25) | −500 (50) | −580 (30) |
ΔEnonpolarsol | −22 (1) | −22 (1) | −16 (1) | −18 (1) | −18 (1) | −18 (1) | −19 (1) |
ΔEpolarsol | 465 (35) | 430 (15) | 350 (20) | 375 (25) | 405 (40) | 345 (60) | 465 (25) |
ΔEattr | −810 | −750 | −640 | −650 | −655 | −665 | −765 |
ΔEvdW/ΔEtot(%) | 51 | 58 | 52 | 53 | 58 | 45 | 54 |
ΔEelect/ΔEtot (%) | 177 | 170 | 164 | 176 | 196 | 156 | 190 |
−ΔEpolarsol/ΔEtot (%) | 135 | 134 | 121 | 136 | 162 | 108 | 152 |
ΔEvdW/ΔEattr (%) | 22 | 24 | 23 | 22 | 22 | 22 | 22 |
ΔEelect/ΔEattr (%) | 76 | 73 | 74 | 75 | 75 | 75 | 76 |
−ΔEpolarsol/ΔEattr (%) | 58 | 57 | 55 | 58 | 62 | 52 | 60 |
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Kurciński, M.; Jarończyk, M.; Lipiński, P.F.J.; Dobrowolski, J.C.; Sadlej, J. Structural Insights into σ1 Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations. Molecules 2018, 23, 456. https://doi.org/10.3390/molecules23020456
Kurciński M, Jarończyk M, Lipiński PFJ, Dobrowolski JC, Sadlej J. Structural Insights into σ1 Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations. Molecules. 2018; 23(2):456. https://doi.org/10.3390/molecules23020456
Chicago/Turabian StyleKurciński, Mateusz, Małgorzata Jarończyk, Piotr F. J. Lipiński, Jan Cz. Dobrowolski, and Joanna Sadlej. 2018. "Structural Insights into σ1 Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations" Molecules 23, no. 2: 456. https://doi.org/10.3390/molecules23020456