Overfill Protection and Hyperdynamics in Adaptively Biased Simulations

Two problems associated with adaptively biased simulations are considered: overfilling and time scale estimation. First, a simple and computationally efficient procedure for limiting the bias fill-depth of any adaptive biasing potential is introduced. The resulting bias potential floods only up to a specified level and avoids bias accumulation in higher regions of free energy. Second, hyperdynamics can be invoked in combination with this depth-limited bias potential to estimate time scales. We argue that allowing the bias to equilibrate to a set depth is one crux in efficient hyperdynamics application. In both simple (alanine dipeptide) and complex (ligand residence) test cases, the useable boost factors are 6–8 times larger when the bias fill depth is directly controlled, as opposed to controlling the update frequency. Update frequency has emerged as a proxy for controlling the fill height of adaptive biases, with infrequent metadynamics being an example. The Kolmogorov–Smirnov test is shown to be insufficient for determining the trustworthiness of a hyperdynamics simulation, and a more robust strategy is described. Overfill limiting and hyperdynamics have been added to the fABMACS project.