Abstract
We explore how a protein's native structure determines its unfolding process. We examine how the local structural features, like shear, and the global structural properties, like the number of soft modes, change during unfolding. Simulations are performed using a Gaussian Network Model (GNM) with bond breaking for both thermal and force-induced unfolding scenarios. We find that unfolding starts in areas of high shear in the native structure and progressively spreads to the low shear regions. Interestingly, analysis of single domain protein families (Chymotrypsin inhibitor and Barnase) reveal that proteins with distinct unfolding pathways exhibit divergent behavior of the number of soft modes during unfolding. This suggests that the number of soft modes might be a valuable tool for understanding thermal unfolding pathways. Additionally, we found a strong link between a protein's overall structural similarity (TM-score) and its unfolding pathways, highlighting the importance of the native structure in determining how a protein unfolds.