LAO+: Focused, Multi-Replica Accelerated Orthogonal Sampling for Robust Binding Free Energy Predictions
Abstract
We introduce Lambda-ABF-OPES+ (LAO+), a multi-replica framework for absolute binding free energy (ABFE) calculations that accelerates both the alchemical transformation and the slow ``orthogonal'' motions coupled to it. At the core of LAO+ is a partitioned λ-dynamics scheme that concentrates sampling on the abrupt rehydration of the binding pocket, the main bottleneck of ligand decoupling, while Hamiltonian replica exchange relays configurations along the entire alchemical path. This drives a fourfold gain in convergence speed for the rate-limiting leg over our previous LAO method, which was itself up to ninefold faster than Lambda-ABF, an overall gain of up to ∼36-fold. Applied to 28 protein--ligand complexes across five targets, LAO+ achieves a root-mean-square error of 0.83~kcal~mol−1 and a correlation of 0.87 with experiment from only 63~ns of sampling per ligand. Moreover, dedicated reservoir replicas accelerate any slow degree of freedom that can be described by a collective variable. We demonstrate this by recovering hidden protein and ligand conformational states, for example in T4 lysozyme, BRD4 and JNK1. Together, these advances make accurate ABFE calculations practical for drug discovery.
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BibTeX
@misc{ansari2026focused,
title = {{LAO+: Focused, Multi-Replica Accelerated Orthogonal Sampling for Robust Binding Free Energy Predictions}},
author = {Narjes Ansari and Florent Hédin and Jérôme Hénin and Jean-Philip Piquemal and Louis Lagardère},
howpublished = {HAL},
year = {2026},
month = oct,
doi = {10.48550/arxiv.2610.20436},
eprint = {2610.20436},
archivePrefix = {arXiv},
url = {https://hal.science/hal-05800490v1},
note = {CC BY-NC-SA 4.0},
}
RIS
TY - UNPB
TI - LAO+: Focused, Multi-Replica Accelerated Orthogonal Sampling for Robust Binding Free Energy Predictions
AU - Narjes Ansari
AU - Florent Hédin
AU - Jérôme Hénin
AU - Jean-Philip Piquemal
AU - Louis Lagardère
PY - 2026
DA - 2026/10/14
PB - HAL
DO - 10.48550/arxiv.2610.20436
UR - https://hal.science/hal-05800490v1
AB - We introduce Lambda-ABF-OPES+ (LAO+), a multi-replica framework for absolute binding free energy (ABFE) calculations that accelerates both the alchemical transformation and the slow ``orthogonal'' motions coupled to it. At the core of LAO+ is a partitioned λ-dynamics scheme that concentrates sampling on the abrupt rehydration of the binding pocket, the main bottleneck of ligand decoupling, while Hamiltonian replica exchange relays configurations along the entire alchemical path. This drives a fourfold gain in convergence speed for the rate-limiting leg over our previous LAO method, which was itself up to ninefold faster than Lambda-ABF, an overall gain of up to ∼36-fold. Applied to 28 protein--ligand complexes across five targets, LAO+ achieves a root-mean-square error of 0.83~kcal~mol^−1 and a correlation of 0.87 with experiment from only 63~ns of sampling per ligand. Moreover, dedicated reservoir replicas accelerate any slow degree of freedom that can be described by a collective variable. We demonstrate this by recovering hidden protein and ligand conformational states, for example in T4 lysozyme, BRD4 and JNK1. Together, these advances make accurate ABFE calculations practical for drug discovery.
ER -