The Role of the Electronic Structure during Protein Folding through Electron Density-Based Quantum Chemical...

One of the major challenges in protein folding is understanding the role that the electronic structure of proteins plays during their folding. We emphasize that the structural and dynamic properties of proteins are extremely important for understanding how their conformational changes occur during folding. However, since the electronic structure is intrinsically related to the atomic structure, further analysis of the electronic structure during folding may assist in the development of methods for predicting protein biological activity. In this study, we applied statistical sampling in molecular dynamics folding trajectories, and subsequent calculations of global and local quantum chemical molecular descriptors calculated by DFT-D3 and semiempirical quantum chemical methods for three fast-folding proteins (NTL9, BBA, and α3D). We observe an intriguing trend in the local hardness per residue (η _j ). Specifically, soft residues do not become softer as the trajectory progresses until they reach the expected softness, and hard residues do not become progressively harder. Rather, a subtle process occurs in which the local hardness fluctuates above and below the final native values for each residue. The point is not that the folded structures have more favorable hard or soft interactions in their residues, but that η _j becomes stable as the conformation approaches the folded state. In addition, we observed that η _j can distinguish non-native from native-like structures, revealing that intrinsic aspects of the electronic structure play a highly relevant role in the protein folding process. These observations could show an electronic structure signature during protein folding.