Interaction with the Surrounding Water Plays a Key Role in Determining the Aggregation Propensity of Proteins

Understanding the molecular determinants of the relative propensities of proteins to aggregate in a cellular environment is a central issue for treating protein‐aggregation diseases and developing peptide‐based therapeutics. Despite the expectation that protein aggregation can largely be attributed to direct protein–protein interactions, a crucial role the surrounding water in determining the aggregation propensity of proteins both in vitro and in vivo was identified. The overall protein hydrophobicity, defined solely by the hydration free energy of a protein in its monomeric state sampling its equilibrium structures, was shown to be the predominant determinant of protein aggregation propensity in aqueous solution. Striking discrimination of positively and negatively charged residues by the surrounding water was also found. This effect depends on the protein net charge and plays a crucial role in regulating the solubility of the protein. These results pave the way for the design of aggregation‐resistant proteins as biotherapeutics. Water, water, everywhere: Understanding the causes of protein aggregation is a central issue for understanding and preventing protein‐aggregation diseases. Most studies to date have focused on the protein sequences without fully addressing the role of the surrounding water molecules. In fact, the interaction of a protein with the water surrounding it was found to play a pivotal role in determining its hydrophobicity and thus its aggregation propensity.