Unsupervised learning of progress coordinates during weighted ensemble simulations: Application to millisecond...

Our method identifies outliers in a latent space model of the system's sampled conformations that is periodically trained using a convolutional variational autoencoder. As a proof of principle, we applied our DL-enhanced WE method to simulate a millisecond protein folding process. To enable rapid tests, our simulations propagated discrete-state synthetic molecular dynamics trajectories using a generative, fine-grained Markov state model. Results revealed that our ″on-the-fly″ DL of outliers enhanced the efficiency of WE by >3-fold in estimating the folding rate constant. Our efforts are a significant step forward in the unsupervised learning of slow coordinates during rare event sampling.