Large energetic barriers can separate stable states in biomolecular systems, which hinders our ability to study rare events. Enhanced sampling methods can be useful to overcome these energy barriers, but often depend on the identification of one or more “order parameters” that describe the event of interest. However, for highly dynamic systems such as ion channels, porins and transporters, suitable order parameters can be difficult to find. Furthermore, the activity of such channels is often driven out of equilibrium by an electric field or a chemical gradient, which prohibits the application of methods that rely on an assumption of local equilibrium. Weighted ensemble (WE) simulations are rare event methods that are particularly well-suited for this class of problems. In WE, a set of independent copies of the system (“walkers”) are run in parallel and are periodically “resampled” using cloning and merging operations. In particular, modern variants of WE (e.g. WExplore and REVO) that employ distance-based resampling methods are useful, as no single order parameter is required, only a means of measuring distance between walkers, which could be defined in a high-dimensional space.  However, for the study of ion transport and the movement of waters leading to activation/inactivation processes in ion channels, new tools are required.  Distance based resampling methods tend to be based on values obtained from specific, predefined atomic indices within a system. This proves problematic for studying ion channels and transport systems because they are dependent on movements of large numbers of ions and water molecules. To overcome this challenge, index-invariant, system-history based distance metrics were developed for WExplore and REVO simulations. Water or ion occupation within predefined bins is recorded every dynamic cycle and this history is used to encourage the further sampling of trajectories with ions or waters occupying previously unexplored bins. History-based sampling methods have proven to be more effective than binning-only based resampling. The validity of these methods has been tested via the hydration-based inactivation process of multiple conformations of the KcsA ion channel. In this process, three waters per monomer occupy the cavity behind the selectivity filter leading to a conformational change that causes channel inactivation. These new tools will allow us to study more complex and biologically-relevant transport-based systems. <br/>

Development of rare-event sampling methods for biomolecular transport systems

2019 Fall National Meeting

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