A physics-inspired approach to the understanding of molecular representations and models

The story of machine learning in general, and its application to molecular design in particular, has been a tale of evolving representations of data. Understanding the implications of the use of a particular representation – including the existence of so-called ‘activity cliffs’ for cheminformatics models – is the key to their successful use for molecular discovery. In this work we present a physics-inspired methodology which exploits analogies between model response surfaces and energy landscapes to richly describe the relationship between the representation and the model. From these similarities, a metric emerges which is analogous to the commonly used frustration metric from the chemical physics community. This new property shows state-of-the-art prediction of model error, whilst belonging to a novel class of roughness measure that extends beyond the known data allowing the trivial identification of activity cliffs even in the absence of related training or evaluation data.