How sticky are our proteins? Quantifying hydrophobicity of the human proteome.

Summary: Proteins tend to bury hydrophobic residues inside their core during the folding process to provide stability to the protein structure and to prevent aggregation. Nevertheless, proteins do expose some 'sticky' hydrophobic residues to the solvent. These residues can play an important functional role, e.g. in protein-protein and membrane interactions. Here, we first investigate how hydrophobic protein surfaces are by providing three measures for surface hydrophobicity: the total hydrophobic surface area, the relative hydrophobic surface area and-using our MolPatch method-the largest hydrophobic patch. Secondly, we analyze how difficult it is to predict these measures from sequence: by adapting solvent accessibility predictions from NetSurfP2.0, we obtain well-performing prediction methods for the THSA and RHSA, while predicting LHP is more challenging. Finally, we analyze implications of exposed hydrophobic surfaces: we show that hydrophobic proteins typically have low expression, suggesting cells avoid an overabundance of sticky proteins. Availability and implementation: The data underlying this article are available in GitHub at https://github.com/ibivu/hydrophobic_patches. Supplementary information: Supplementary data are available at Bioinformatics Advances online.

The hydrophobic effect characterises the thermodynamic signature of amyloid fibril growth.

Many proteins have the potential to aggregate into amyloid fibrils, protein polymers associated with a wide range of human disorders such as Alzheimer's and Parkinson's disease. The thermodynamic stability of amyloid fibrils, in contrast to that of folded proteins, is not well understood: the balance between entropic and enthalpic terms, including the chain entropy and the hydrophobic effect, are poorly characterised. Using a combination of theory, in vitro experiments, simulations of a coarse-grained protein model and meta-data analysis, we delineate the enthalpic and entropic contributions that dominate amyloid fibril elongation. Our prediction of a characteristic temperature-dependent enthalpic signature is confirmed by the performed calorimetric experiments and a meta-analysis over published data. From these results we are able to define the necessary conditions to observe cold denaturation of amyloid fibrils. Overall, we show that amyloid fibril elongation is associated with a negative heat capacity, the magnitude of which correlates closely with the hydrophobic surface area that is buried upon fibril formation, highlighting the importance of hydrophobicity for fibril stability.