Computer Simulations of the Interaction of Anaesthetic Molecules Fentanyl and Propofol with Biological Membranes

Computational techniques are well placed to investigate materials and processes in the body that are difficult to access experimentally. In this work we have used all-atom computer simulations to predict the structures and behaviours with biological membranes in the cell of two important molecules in the process to induce anaesthesia, i.e. propofol and fentanyl. The lipid membrane is considered a crucial component of opioid general anaesthesia and detailed atomic-level insight into the drug-membrane interactions could lead to a better understanding how different drugs exert their anaesthetic properties.<br/>First, we have investigated the opioid analgesic fentanyl on its own, using extensive umbrella sampling molecular dynamics simulations to study the permeation process into a variety of simple phospholipid membrane models, accurately predicting the permeability coefficients, followed by its interactions with the <i>Gloeobacter violaceus</i> ligand-gated ion channel (GLIC). The simulations have identified multiple extracellular fentanyl binding sites, which are different from the transmembrane general anaesthetic binding sites observed for propofol and other general anaesthetics, including a novel fentanyl binding site within the GLIC which results in conformational changes that inhibit conduction through the channel.<br/>The second part of our study explicitly includes the interactions between fentanyl and propofol. General anaesthesia is a multi-drug process and our work provides the first insight into how different components in the anaesthesia process interact with each other in a relevant biological environment. For example, using flooding style and gaussian accelerated molecular dynamics (GaMD) simulations, we show fentanyl acting as a stabiliser that holds propofol within binding sites in GLIC, whereas the simulations were also able to show the pathway by which propofol physically blocks the ion-conducting channel pore, which has previously been suggested as a mechanism for ion channel modulation by propofol.