In this work, we propose a careful and thorough analysis of the chemical bond nature in high nuclearity metal carbonyl clusters having semi-interstitial main group atoms. We investigated the species [Co6X(CO)(16)](-) (X = As, P), known for a rather interesting conformational flexibility of the cluster (leading to open or closed cages) and a corresponding polymorphism in the solid state (observed at least for X = As). The factors that trigger the molecular isomerism and the nature of X-Co and Co-Co interactions emerge from theoretical calculations and high resolution X-ray diffraction. Both energy and charge density atomic partitioning (QTAIM, EDA, IQA) are employed for this analysis, with the aim of revealing the stabilizing/destabilizing factors of the interaction between the cage and the semi-interstitial atoms in the various conformations.