Mutation-induced biophysical destabilization as a key contributor to cancer-driving potential in the human structural protein interactome

A systems-level investigation of mutation-induced perturbations in the human structural protein interactome, the network of structurally resolved protein-protein interactions in human cells, provides mechanistic insight into the complexity underlying oncogenesis. Mutations can destabilize protein folding or specific protein-protein interactions, resulting in loss-of-function effects within the interactome. Although such network-level loss-of-function consequences may contribute to oncogenesis, previous studies have largely examined either folding or binding destabilization in isolation. Here, we performed structural and free-energy calculations to assess the impact of interactome-wide cancer-associated missense mutations on protein-folding stability and protein-binding stability. We assessed the cancer-driving potential of destabilizing mutations using a "fold difference" metric, defined as the ratio between the fractions of destabilizing mutations in datasets of cancer-associated and non-pathogenic mutations. We observed a strong positive correlation between biophysical destabilization and cancer-driving potential, with folding-destabilizing ("quasi-null") and binding-destabilizing ("edgetic") mutations within cancer-driving genes causing stronger structural and functional effects than those across the entire cancer genome. Our findings align with the expectation that cancer-driving genes are enriched in driver mutations and suggest that biophysical destabilization is a key contributor to cancer-driving potential. Overall, our study provides a biophysical perspective on the loss-of-function implications of destabilizing mutations across the interactome, enhancing comprehension of the intricate processes driving oncogenesis.