Exploration of ligand (un)binding trajectories with Rosetta
- 1Institute for Drug Discovery, Leipzig University, Leipzig, Germany
Abstract
Ligand transport through proteins underlies many aspects of molecular function, but its detailed mechanisms remain largely inaccessible to direct observation. Molecular dynamics simulations could close this gap, but are computationally too demanding for practical purposes, including filtering stages of enzyme design pipelines. Simplified docking-based approaches might be informative, but sometimes the oversimplifications required for high throughput applications might lead to unreliable predictions. Here we present RosettaLigand PathFinder (RLPF), a fast and practical tool explicitly built to ensure conformational continuity of the ligand trajectory, protein and ligand flexibility, and robustness of every run. Built using a flexible RosettaScripts XML interface, it enables fine-grained control over all simulation parameters and adaptability for a wide range of use cases. Applied to several representative systems, RLPF reproduced established transport features and mutation effects, highlighting its ability to produce biologically relevant insights and serve as a filter in enzyme design campaigns. Wide customizability and well-defined scope of RLPF make it a useful addition to the family of tools to study the dynamics of interactions between small molecules and proteins.
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BibTeX
@misc{zlobin2026exploration,
title = {{Exploration of ligand (un)binding trajectories with Rosetta}},
author = {A. Zlobin and P. Eisenhuth and V. Ferrario and J. Meiler},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.757317},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757317v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Exploration of ligand (un)binding trajectories with Rosetta
AU - A. Zlobin
AU - P. Eisenhuth
AU - V. Ferrario
AU - J. Meiler
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.757317
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.757317v1
AB - Ligand transport through proteins underlies many aspects of molecular function, but its detailed mechanisms remain largely inaccessible to direct observation. Molecular dynamics simulations could close this gap, but are computationally too demanding for practical purposes, including filtering stages of enzyme design pipelines. Simplified docking-based approaches might be informative, but sometimes the oversimplifications required for high throughput applications might lead to unreliable predictions. Here we present RosettaLigand PathFinder (RLPF), a fast and practical tool explicitly built to ensure conformational continuity of the ligand trajectory, protein and ligand flexibility, and robustness of every run. Built using a flexible RosettaScripts XML interface, it enables fine-grained control over all simulation parameters and adaptability for a wide range of use cases. Applied to several representative systems, RLPF reproduced established transport features and mutation effects, highlighting its ability to produce biologically relevant insights and serve as a filter in enzyme design campaigns. Wide customizability and well-defined scope of RLPF make it a useful addition to the family of tools to study the dynamics of interactions between small molecules and proteins.
ER -