Path sampling methods for protein-ligand binding kinetics
Wouter Vervust
∗1,2and An Ghysels
1,21Biofluid, Tissue and Solid Mechanics for Medical Applications - Ghent University – Belgium
2Department of Electronics and Information Systems - Ghent University – Belgium
Abstract
In this study, state-of-the-art molecular dynamics simulation techniques are used to ex- tract the binding kinetics of protein-ligand complexes. Kinetic parameters, such as the (un)binding rate constants and residence time, have recently been shown to be important for predicting thein vivo efficacy of candidate drug molecules. Computational tools to predict binding kinetics are therefore needed in the screening stage of the drug-design pipeline, where the combination of thermodynamic and kinetic selectivity results in better drug candidates.
However, the time-dependent nature of kinetics makes it a challenging subject for current computational resources.
Replica Exchange Transition Interface Sampling (RETIS) [1] is an exact path sampling method. RETIS uses an initial trajectory to generate new trajectories using shooting moves, which are accepted or rejected according to the Metropolis-Hastings algorithm. RETIS al- lows paths to be exchanged between different path ensembles, which greatly enhances the sampling efficiency. This is a promising feature to tackle the known challenge of orthogo- nal degrees of freedom (DoFs), where a user-defined, low-dimensional reaction coordinate misses important free energy contributions in these orthogonal DoFs, resulting in inaccu- rate kinetics. RETIS is in principle reaction-coordinate independent and requires only the definition of an order parameter that distinguishes between the bound and unbound states of the protein-ligand complex. RETIS delivers reactive trajectories with the true dynamics (i.e. no bias potential is used), which also allows to extract qualitative information of the (un)binding process.
The method is currently set up for the ABL-imatinib complex. ABL is a kinase protein important for cell regulation, and imatinib is the first-line drug for patients with chronic myeloid leukemia, where the fusion oncoprotein BCR-ABL renders the ABL kinase domain in a constitutively active state. In the future, we envision to extend the methodology to general protein-ligand complexes.
Reference: [1] R. Cabriolu, K. M. Skjelbred Refsnes, P. G. Bolhuis, and T. S. Van Erp, ”Foun- dations and latest advances in replica exchange transition interface sampling,” J. Chem.
Phys., vol. 147, no. 15, 2017, doi: 10.1063/1.4989844.
∗Speaker
