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

TL;DR

This study quantifies the hydrophobic surface exposure of human proteins using three measures, evaluates prediction methods from sequence data, and explores the biological implications of hydrophobicity on protein expression levels.

Contribution

It introduces three novel measures for protein surface hydrophobicity and assesses the predictability of these measures from sequence data.

Findings

Hydrophobic surface measures can be predicted with high accuracy from sequence.

Hydrophobic proteins tend to have lower expression levels.

The largest hydrophobic patch is more challenging to predict than other measures.

Abstract

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, for example in protein-protein and membrane interactions. Here, we 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 analyse 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 difficult. Finally, we analyse implications of exposed hydrophobic surfaces: we show that hydrophobic proteins typically have low expression, suggesting cells avoid an overabundance of sticky proteins.