Number of Hydrogen Bonds per Unit Solvent Accessible Surface Area: A Descriptor of Functional States of Proteins.

Proteins function close to native and near-native conformations. These states are evolutionarily selected to ensure the effect of mutations is minimized. The structural organization of a protein is hierarchical and modular, which reduces the dimensionality of the configurational space of the native states. Thus, finding appropriate descriptors that define the native state among all possible states of a protein is a problem of immense interest. The present study explores the correlation between solvent accessible surface areas (SASAs) and different intraprotein as well as protein-water hydrogen bonds of 55 single-chain globular proteins from four different structural classes (all α, all β, α+β, and α/β), 16 multichain proteins, and 4 macromolecular complexes. A systematic analysis of the solvent accessible surface area and intraprotein and protein-water hydrogen bonds suggests a linear relationship between SASAs and hydrogen bonds. The number of protein-water hydrogen bonds per unit SASA ranges from 3 to 4 for all the different structural protein classes. In contrast, the number of intramolecular hydrogen bonds per unit SASA, including the mainchain-mainchain, mainchain-sidechain, and sidechain-sidechain, varies between 0.75 to 2. The solvation free energy of a protein linearly decreases with SASA. Our study also shows that the solvation free energy/SASA varies from -75 to -105 kJ mol -1 nm -2 across all the native states studied here. The number conservancy of intraprotein hydrogen bonds per unit SASA possibly imparts structural stability to the native structure. On the other hand, 3-4 protein-water hydrogen bonds per unit SASA are possibly required to maintain a balance between the solubility and functionality of the native states. This study provides a basis for synthetic biologists to design new folds with improved functionality.