Extending path memory to improve kinetics calculations in rare molecular processes

Molecular dynamics (MD) simulations serve as a computational microscope to study the intricate kinetics of crucial biological processes, such as the binding of a cancer drug molecule or permeation of a molecule through cell membranes. One of the main challenges in this field is the significant disparity in timescales: while these processes occur rapidly, simulating them can require years of CPU time. To solve this, we use Transition Interface Sampling (TIS), an enhanced sampling algorithm that bridges the gap between these widely separated timescales. This is done by quantifying the progress of a reaction using a single variable and placing checkpoints ("interfaces") along the way, after which we cleverly sample MD trajectories ("paths") at strategic points. However, TIS can struggle with simulating biological processes with complex energy landscapes, often leading to paths getting stuck in metastable states, resulting in lengthy simulation times. PPTIS (Partial Path TIS) removes this problem by cutting paths short, which unfortunately also truncates the history of particle trajectories, potentially leading to a significant loss in accuracy. To tackle these shortcomings we introduce StapleTIS, an innovative approach that preserves essential trajectory memory while keeping paths manageable in length. The paths are terminated by turns (occurring when encountering an energetic barrier for example) on both sides, mimicking the shape of a staple. This ensures paths "remember" a longer segment of their trajectory, enabling them to navigate a potential energy landscape more efficiently and giving us more accurate information about the kinetics of the system. We demonstrate the effectiveness of StapleTIS using 1D and 2D toy systems, achieving performance comparable to traditional TIS. Our next steps involve applying this method to real-world biological systems to obtain valuable information about their kinetics, ultimately enriching our knowledge about various biological mechanisms.