# Strain Problems got you in a Twist? Try StrainRelief: A Quantum-Accurate Tool for Ligand Strain Calculations

arXiv: https://arxiv.org/abs/2503.13352 · HTML: https://mlsanity.com/paper/2503.13352/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 5 of its 43 references that are in the map.
- First posted on arXiv 17 Mar 2025.

## Builds on (most cited first, 5 of 5)

- [E(3)-Equivariant Graph Neural Networks for Data-Efficient and Accurate Interatomic Potentials](https://mlsanity.com/paper/2101.03164/) (2021)
- [MACE: Higher Order Equivariant Message Passing Neural Networks for Fast and Accurate Force Fields](https://mlsanity.com/paper/2206.07697/) (2022)
- [Machine Learning Force Fields](https://mlsanity.com/paper/2010.07067/) (2020)
- [SPICE, A Dataset of Drug-like Molecules and Peptides for Training Machine Learning Potentials](https://mlsanity.com/paper/2209.10702/) (2022)
- [On the design space between molecular mechanics and machine learning force fields](https://mlsanity.com/paper/2409.01931/) (2024)

## Abstract (arXiv)

Ligand strain energy, the energy difference between the bound and unbound conformations of a ligand, is an important component of structure-based small molecule drug design. A large majority of observed ligands in protein-small molecule co-crystal structures bind in low-strain conformations, making strain energy a useful filter for structure-based drug design. In this work we present a tool for calculating ligand strain with a high accuracy. StrainRelief uses a MACE Neural Network Potential (NNP), trained on a large database of Density Functional Theory (DFT) calculations to estimate ligand strain of neutral molecules with quantum accuracy. We show that this tool estimates strain energy differences relative to DFT to within 1.4 kcal/mol, more accurately than alternative NNPs. These results highlight the utility of NNPs in drug discovery, and provide a useful tool for drug discovery teams.