Extending quantum-mechanical benchmark accuracy to biological ligand-pocket interactions

Mirela Puleva, Leonardo Medrano Sandonas (), Balázs D. Lőrincz, Jorge Charry, David M. Rogers, Péter R. Nagy () and Alexandre Tkatchenko ()
Additional contact information
Mirela Puleva: University of Luxembourg
Leonardo Medrano Sandonas: University of Luxembourg
Balázs D. Lőrincz: Budapest University of Technology and Economics
Jorge Charry: University of Luxembourg
David M. Rogers: Oak Ridge National Laboratory
Péter R. Nagy: Budapest University of Technology and Economics
Alexandre Tkatchenko: University of Luxembourg

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Predicting the binding affinity of ligands to protein pockets is key in the drug design pipeline. The flexibility of ligand-pocket motifs arises from a range of attractive and repulsive electronic interactions during binding. Accurately accounting for all interactions requires robust quantum-mechanical (QM) benchmarks, which are scarce for ligand-pocket systems. Additionally, disagreement between “gold standard” Coupled Cluster (CC) and Quantum Monte Carlo (QMC) methods casts doubt on many benchmarks for larger non-covalent systems. We introduce the “QUantum Interacting Dimer” (QUID) benchmark framework containing 170 non-covalent (non-)equilibrium systems modeling chemically and structurally diverse ligand-pocket motifs. Symmetry-adapted perturbation theory shows that QUID broadly covers non-covalent binding motifs and energetic contributions. Robust binding energies are obtained using complementary CC and QMC methods, achieving agreement of 0.5 kcal/mol. The benchmark data analysis reveals that several dispersion-inclusive density functional approximations provide accurate energy predictions, though their atomic van der Waals forces differ in magnitude and orientation. Contrarily, semiempirical methods and empirical force fields require improvements in capturing non-covalent interactions (NCIs) for out-of-equilibrium geometries. The wide span of NCIs, highly accurate interaction energies, and analysis of molecular properties take QUID beyond the “gold standard” for QM benchmarks of ligand-protein systems.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63587-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63587-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63587-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().