The Reference Set Is Not the Answer Set: GEOM-DRUGS Is Missing Low-Energy Conformers on Its Own Energy Surface

Abstract

Machine-learned conformer generators are scored on GEOM-DRUGS by proximity to a reference ensemble that standard benchmark metrics implicitly treat as ground truth. We test whether that finite set is complete on the GFN2-xTB surface used to construct it. Across five public generators, settled, low-energy structures remain outside the $0.75$\,Å reference radius after removing reflections, incorrect stereochemistry, and post-relaxation connectivity changes ($2.3$--$7.0\%$ of submitted conformers, depending on architecture). In a targeted DFT audit, $107$ of $113$ chemically screened novel/reference pairs remain outside that radius after full $ω$B97X-D3BJ re-optimization. A threshold-free complementary test needs no radius and no energy window at all: on $15.0\%$ $[8.0, 22.0]$ of molecules some generator has already found a chemically intact structure lying below the \emph{entire} released ensemble. A complementary CREST search reproduces the minimum released in $65$ of $69$ molecules, and in $11$ of them it reaches more than $0.5$\,kcal/mol below the complete released ensemble. Augmenting the references with conformers proposed by held-out architectures raises absolute coverage-precision for every generator tested, by $1.48$--$2.99$ points. Together, these results show that GEOM-DRUGS precision is sensitive not only to generator quality but also to incomplete reference support.