Exact Kinetics of Drug Permeation Using Transition Interface Sampling

We implement ∞RETIS, the most advanced variant of the replica exchange transition interface sampling (RETIS) algorithm, which employs asynchronous swapping moves in the infinite swapping limit. This design enables highly efficient parallelization across CPUs and GPUs, resulting in a substantial acceleration in convergence. Using molecular dynamics (MD) simulations, we apply this method to investigate the membrane permeation of 5-aminolevulinic acid (5-ALA), a hydrophilic drug widely used in photodynamic therapy (PDT) and fluorescence-guided surgery. Key kinetic properties, including the permeability and mean first passage time, are computed from the resulting unbiased trajectories. Furthermore, the mechanistic details of 5-ALA permeation are explored, showing the impact of the 5-ALA orientation and its hydration by water molecules inside the membrane on whether a trajectory contributes to successful membrane crossing. By resolving the full kinetic mechanism of 5-ALA permeation through a phospholipid bilayer, this study showcases the power of ∞RETIS in addressing rare event dynamics in biologically and pharmaceutically relevant systems.