7939
2020
2020
eng
1443
1452
18
46
article
Taylor and Francis
0
2020-11-08
2020-11-08
--
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.
Molecular Simulation
10.1080/08927022.2020.1839660
yes
publish
urn:nbn:de:0297-zib-78437
Sourav Ray
Erlinda Körnig
Vikram Sunkara
Christof Schütte
Marcus Weber
Numerical Mathematics
Schütte, Christof
Weber, Marcus
MODAL-MedLab
Sunkara, Vikram
MODAL-Gesamt
Ray, Sourav
Mathematics for Life and Materials Science
Modeling and Simulation of Complex Processes