The deformation energy gap in computational drug design: why interaction energy alone cannot rank drug candidates and a thermodynamic correction protocol.

Authors

Iqra Malik, Muhammad Javid Iqbal

Published in

Journal of molecular modeling. Volume 32. Issue 7. Jun 25, 2026. Epub Jun 25, 2026.

Abstract

DFT calculations are increasingly combined with molecular docking to rank drug candidates, yet most studies report the interaction energy (ΔE_int), computed at the complex geometry, as a surrogate for binding affinity. This quantity omits the deformation energy (ΔE_def): the thermodynamic penalty of distorting both partners from their free-state geometries into their bound conformations. Because ΔE_def is always positive (typically 2-20 kcal mol^-1) and molecule-dependent, its omission systematically overestimates binding strength and can reverse predicted rank-orderings. We present the energetic decomposition ΔEbind = ΔEint + ΔEdef, demonstrate using published crystallographic strain data from over 3,000 protein-ligand complexes that deformation energies do not cancel between structurally distinct ligands, and propose a minimal five-step correction protocol applicable to any DFT-based drug design study. The protocol requires only two additional geometry optimizations beyond the standard workflow, adding only modest additional computational cost. This work does not introduce new computational data; it highlights an energetic inconsistency in common computational practice and provides a straightforward correction to enable more consistent electronic binding energy evaluation and improved candidate comparison.  METHODS: The analysis is based on the supramolecular energy decomposition framework and the activation strain model (ASM), in which binding energy is partitioned into interaction and deformation (strain) components using standard variational principles. No new DFT calculations are reported. The argument draws on published conformational strain datasets obtained at various DFT levels and molecular mechanics force fields from crystallographic analyses of the PDBBind database. The proposed correction protocol is general and can be applied with any DFT functional, basis set, and quantum chemistry software package (e.g., Gaussian, ORCA, or equivalent).

PMID:
42348003
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.