A Two-Ended Data-Driven Accelerated Sampling Method for Exploring the Transition Pathways between Two Known States of Protein

Conformational transitions of protein between different states are often associated with their biological functions. These dynamic processes, however, are usually not easy to be well characterized by experimental measurements, mainly because of inadequate temporal and spatial resolution. Meantime, sampling of configuration space with molecular dynamics (MD) simulations is still a challenge. Here we proposed a robust two-ended data-driven accelerated (teDA2) conformational sampling method, which drives the structural change in an adaptively updated feature space without introducing a bias potential. teDA2 was applied to explore adenylate kinase (ADK), a model with well characterized "open" and "closed" states. A single conformational transition event of ADK could be achieved within only a few or tens of nanoseconds sampled with teDA2. By analyzing hundreds of transition events, we reproduced different mechanisms and the associated pathways for domain motion of ADK reported in the literature. The multiroute characteristic of ADK was confirmed by the fact that some metastable states identified with teDA2 resemble available crystal structures determined at different conditions. This feature was further validated with Markov state modeling with independent MD simulations. Therefore, our work provides strong evidence for the conformational plasticity of protein, which is mainly due to the inherent degree of flexibility. As a reliable and efficient enhanced sampling protocol, teDA2 could be used to study the dynamics between functional states of various biomolecular machines.