How to calculate pH-dependent binding rates for receptor-ligand systems based on thermodynamic simulations with different binding motifs
- Molecular simulations of ligand–receptor interactions are a computational challenge, especially when their association- (‘on’-rate) and dissociation- (‘off’-rate) mechanisms are working on vastly differing timescales. One way of tackling this multiscale problem is to compute the free-energy landscapes, where molecular dynamics (MD) trajectories are used to only produce certain statistical ensembles. The approach allows for deriving the transition rates between energy states as a function of the height of the activation-energy barriers. In this article, we derive the association rates of the opioids fentanyl and N-(3-fluoro-1-phenethylpiperidin-4-yl)-N-phenyl propionamide (NFEPP) in a μ-opioid receptor by combining the free-energy landscape approach with the square-root-approximation method (SQRA), which is a particularly robust version of Markov modelling. The novelty of this work is that we derive the association rates as a function of the pH level using only an ensemble of MD simulations. We also verify our MD-derived insights by reproducing the in vitro study performed by the Stein Lab.
Author: | Sourav Ray, Vikram SunkaraORCiD, Christof Schütte, Marcus Weber |
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Document Type: | Article |
Parent Title (German): | Molecular Simulation |
Volume: | 46 |
Issue: | 18 |
First Page: | 1443 |
Last Page: | 1452 |
Publisher: | Taylor and Francis |
Date of first Publication: | 2020/11/08 |
Preprint: | urn:nbn:de:0297-zib-78437 |
DOI: | https://doi.org/10.1080/08927022.2020.1839660 |