Absolute binding free energy (ABFE) is a pivotal concept in computational biology and medicinal chemistry, providing a rigorous and transparent framework to quantify the PL interactions. The modeling of binding affinity through molecular simulation has been an active research area, aiming to achieve a holy grail in computer chemistry. With recent strides in computational hardware and advanced algorithms, we have witnessed how ABFE calculations are influencing molecular design and screening in drug discovery and beyond . For instance, in 2022, Wu et al. utilized ABFE calculations to guide scaffold hopping in the design of PDE5 inhibitors , ultimately leading to the discovery of the potent lead L12 with an IC 50 of 8.3 nmol/L and a distinct scaffold compared to the initial compounds. In 2023, Biggin et al. proposed a novel method that integrates ABFE calculations to enhance fragment-based molecular optimization, further highlighting the vast potential of ABFE 2 .