Coarse-Grained MD Simulations of Opioid Interactions with the μ-Opioid Receptor and the Surrounding Lipid Membrane

• Published in: Biophysica 2023-06, Vol.3 (2), p.263-275
• Main Authors: Ray, Sourav, Fackeldey, Konstantin, Stein, Christoph, Weber, Marcus
• Format: Article
• Language: English
• Subjects: Analgesics; Bars; Chemical bonds; coarse-grain; Fentanyl; Ligands; Lipids; membrane bilayer; molecular dynamics; Narcotics; opioid; Proteins; Simulation; SqrA; μ-opioid receptor
• ISSN: 2673-4125; 2673-4125
• DOI: 10.3390/biophysica3020017

In our previous studies, a new opioid (NFEPP) was developed to only selectively bind to the μ-opoid receptor (MOR) in inflamed tissue and thus avoid the severe side effects of fentanyl. We know that NFEPP has a reduced binding affinity to MOR in healthy tissue. Inspired by the modelling and simulations performed by Sutcliffe et al., we present our own results of coarse-grained molecular dynamics simulations of fentanyl and NFEPP with regards to their interaction with the μ-opioid receptor embedded within the lipid cell membrane. For technical reasons, we have slightly modified Sutcliffe’s parametrisation of opioids. The pH-dependent opioid simulations are of interest because while fentanyl is protonated at the physiological pH, NFEPP is deprotonated due to its lower pKa value than that of fentanyl. Here, we analyse for the first time whether pH changes have an effect on the dynamical behaviour of NFEPP when it is inside the cell membrane. Besides these changes, our analysis shows a possible alternative interaction of NFEPP at pH 7.4 outside the binding region of the MOR. The interaction potential of NFEPP with MOR is also depicted by analysing the provided statistical molecular dynamics simulations with the aid of an eigenvector analysis of a transition rate matrix. In our modelling, we see differences in the XY-diffusion profiles of NFEPP compared with fentanyl in the cell membrane.