Efficient sampling of conformational space via unbiased molecular dynamics in multiple low-dimensional collective variable spaces

Molecular dynamics (MD) simulations struggle to resolve rare conformational transitions hindered by high energy barriers. We introduce the Equivalent Weight Method (EWM), an enhanced sampling framework that combines dynamic trajectory segmentation and adaptive weight balancing guided by real-time density analysis. EWM enables comprehensive conformational exploration by strategically combining multiple low-dimensional collective variable (CV) spaces with real-time CV augmentation. Validated across model potentials and a coarse-grained calmodulin system, EWM demonstrates marked efficiency gains over conventional MD simulations, while preserving the system's natural thermodynamic and kinetic properties. This approach circumvents the limitations of fixed high-dimensional CV representations, offering a robust balance between computational efficiency and physical accuracy.