Deep-Learning-Assisted Enhanced Sampling for Exploring Molecular Conformational Changes.

We present a novel strategy to explore conformational changes and identify stable states of molecular objects, eliminating the need for a priori knowledge. The approach applies a deep learning method to extract information about the movement modes of the molecular object from a short, high-dimensional, and parameter-free preliminary enhanced-sampling simulation. The gathered information is described by a small set of deep-learning-based collective variables (dCVs), which steer the production-enhanced-sampling simulation. Considering the challenge of adequately exploring the configurational space using the low-dimensional, suboptimal dCVs, we incorporate a method designed for ergodic sampling, namely, Gaussian-accelerated molecular dynamics (MD), into the framework of CV-based enhanced sampling. MD simulations on both toy models and nontrivial examples demonstrate the remarkable computational efficiency of the strategy in capturing the conformational changes of molecular objects without a priori knowledge. Specifically, we achieved the blind folding of two fast folders, chignolin and villin, within a time scale of hundreds of nanoseconds and successfully reconstructed the free-energy landscapes that characterize their reversible folding. All in all, the presented strategy holds significant promise for investigating conformational changes in macromolecules, and it is anticipated to find extensive applications in the fields of chemistry and biology.