Bias-Deletion Metadynamics Revealing Volume–Rotation Coupling Mechanisms in Metal–Organic Frameworks

Enhanced sampling methods in molecular dynamics simulations often struggle to handle interdependent modes in complex systems. This leads to nonergodic simulations characterized by hysteresis, dependence on initial configurations, and the need for intricate collective variables. We introduce bias-deletion metadynamics, a technique that conditionally deletes biases to enable repeated exploration of transition pathways and systematic refinement of the sampled configurational space. The underlying free-energy surface is accurately recovered by rescaling the resulting probability distribution by the number of repetitions. We benchmark bias-deletion metadynamics on alanine dipeptide, demonstrating its ability to handle recurrent rotational motion where conventional metadynamics can fail. We further show its power by resolving the distinct phases of CAU-13 using only a volume bias, a known challenge for other methods. Finally, by applying this approach to a series of isoreticular metal-organic frameworks (MIL-53(Al), NU-2002, MIL-cub, and NU-2000), we uncover the intricate coupling between linker rotation and framework volume, revealing how linker dimensionality dictates volume-specific rotational preferences.