Hyperspatial Sampling: Circumventing Free-Energy Barriers via Replica Exchange with Extra Dimensions
TL;DR
HS-REX achieves enhanced conformational sampling of not only the slow backbone dihedral angles, but also both chiral configurations of the molecule, which are sterically inaccessible to standard sampling in three dimensions, demonstrating enhanced ergodic sampling over conventional temperature replica exchange.
Abstract
Simulating systems with rugged free-energy landscapes remains a central challenge in computational physics and chemistry. We introduce hyperspatial replica exchange (HS-REX), an enhanced sampling method in which the physical system is artificially extended by additional spatial dimensions. In higher dimensions, free-energy barriers can be circumvented through paths that are geometrically inaccessible in the original space. Restricting the penalty to only solute atoms dramatically reduces the number of replicas required for solvated systems compared to standard temperature replica exchange, a feature especially relevant for biological applications. As proof of concept, we demonstrate the method on a double-well model system and on alanine dipeptide in explicit water as benchmark system. In the latter case, HS-REX achieves enhanced conformational sampling of not only the slow backbone dihedral angles, but also both chiral configurations of the molecule, which are sterically inaccessible to standard sampling in three dimensions. This demonstrates enhanced ergodic sampling over conventional temperature replica exchange.