Accelerated Structural Prediction of Flexible Protein-Ligand Complexes: The SLICE Method

Using existing and academically available software, we present a new method for the structural prediction of binding events containing flexible protein targets. SLICE (Selective Ligand-Induced Conformational Ensemble) combines opportunistic stochastic jumps of ligand position with standard molecular dynamics to model the induced-fit binding of ligands starting with unbound host coordinates. To induce the structural adaptations of the complex at the binding site, conformational jumps in ligand position are selected in SLICE from structures generated by a docking software. Multiple binding trajectories from the docking set are followed using molecular dynamics for a set time to relax the host structure and generate new host poses. A new configurational jump is made on the set of newly generated host poses. The process is then repeated. The method was implemented with AutoDock Vina as the docking method, Vina scores as the selection criterion, and Amber code for molecular dynamics and applied to several test systems. A system consisting of Chromobox protein homologue 8 (CBX8) and its small peptide ligand, H3K9Me₃, for which the final (bound) configuration is known, is used for verifying SLICE in the present setup. The setup was also applied to several nonpeptide molecules on known difficult flexible targets exhibiting a large disparity between apo and holo host states. The SLICE simulations provide a promising approach to generate induced-fit configurations compared to existing long (microsecond) classical and accelerated dynamics approaches in all the test systems considered here. However, further optimization of SLICE parameters is required for replicating crystal structure coordinates for some systems. We discuss in the following pages the various SLICE parameters and how they can be optimized for the system at hand.