A deep encoder–decoder framework for identifying distinct ligand binding pathways

The pathway(s) that a ligand would adopt en route to its trajectory to the native pocket of the receptor protein act as a key determinant of its biological activity. While Molecular Dynamics (MD) simulations have emerged as the method of choice for modeling protein-ligand binding events, the high dimensional nature of the MD-derived trajectories often remains a barrier in the statistical elucidation of distinct ligand binding pathways due to the stochasticity inherent in the ligand's fluctuation in the solution and around the receptor. Here, we demonstrate that an autoencoder based deep neural network, trained using an objective input feature of a large matrix of residue-ligand distances, can efficiently produce an optimal low-dimensional latent space that stores necessary information on the ligand-binding event. In particular, for a system of L99A mutant of T4 lysozyme interacting with its native ligand, benzene, this deep encoder-decoder framework automatically identifies multiple distinct recognition pathways, without requiring user intervention. The intermediates involve the spatially discrete location of the ligand in different helices of the protein before its eventual recognition of native pose. The compressed subspace derived from the autoencoder provides a quantitatively accurate measure of the free energy and kinetics of ligand binding to the native pocket. The investigation also recommends that while a linear dimensional reduction technique, such as time-structured independent component analysis, can do a decent job of state-space decomposition in cases where the intermediates are long-lived, autoencoder is the method of choice in systems where transient, low-populated intermediates can lead to multiple ligand-binding pathways.