Memory-resolved prediction of ligand residence times on the minutes timescale
Abstract
AI-enabled computational drug discovery is advancing rapidly in predicting molecular structures, binding poses and affinities, but ligand dissociation kinetics remain harder to access. Bound-state residence time, important for biological response and kinetic selectivity, is not fixed by equilibrium affinity but depends on the dissociation free-energy landscape and dissipative friction effects. Here, we show that restrained umbrella-sampling trajectories can be used to calculate residence times on the minutes timescale. Time-resolved coordinate fluctuations yield friction profiles that incorporate non-Markovian effects on dissociation kinetics. Combining them with the free-energy profile, we predict a residence time of τres = 275 s for the adenosine A2A receptor with ZM241385 (comparable to the experimental value of 125 s) and reproduce the experimental ranking of wild type and two receptor mutants. For HSP90 with compound 18 and RNase S with the S15 peptide, we predict τres = 2,169 s and 2,259 s (experimental values are 833 s and 2,439 s). Neglecting memory effects on residence kinetics overestimates τres by factors of 2.6 to 29.
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BibTeX
@misc{batebi2026memoryresolved,
title = {{Memory-resolved prediction of ligand residence times on the minutes timescale}},
author = {Hossein Batebi and Lucas Tepper and Roland R. Netz},
howpublished = {arXiv},
year = {2026},
month = oct,
doi = {10.48550/arxiv.2610.20271},
eprint = {2610.20271},
archivePrefix = {arXiv},
url = {https://arxiv.org/abs/2610.20271},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Memory-resolved prediction of ligand residence times on the minutes timescale
AU - Hossein Batebi
AU - Lucas Tepper
AU - Roland R. Netz
PY - 2026
DA - 2026/10/14
PB - arXiv
DO - 10.48550/arxiv.2610.20271
UR - https://arxiv.org/abs/2610.20271
AB - AI-enabled computational drug discovery is advancing rapidly in predicting molecular structures, binding poses and affinities, but ligand dissociation kinetics remain harder to access. Bound-state residence time, important for biological response and kinetic selectivity, is not fixed by equilibrium affinity but depends on the dissociation free-energy landscape and dissipative friction effects. Here, we show that restrained umbrella-sampling trajectories can be used to calculate residence times on the minutes timescale. Time-resolved coordinate fluctuations yield friction profiles that incorporate non-Markovian effects on dissociation kinetics. Combining them with the free-energy profile, we predict a residence time of τ_res = 275 s for the adenosine A_2A receptor with ZM241385 (comparable to the experimental value of 125 s) and reproduce the experimental ranking of wild type and two receptor mutants. For HSP90 with compound 18 and RNase S with the S15 peptide, we predict τ_res = 2,169 s and 2,259 s (experimental values are 833 s and 2,439 s). Neglecting memory effects on residence kinetics overestimates τ_res by factors of 2.6 to 29.
ER -