The hydrophobic temperature dependence of amino acids directly calculated from protein structures

PLoS Comput Biol. 2015 May 22;11(5):e1004277. doi: 10.1371/journal.pcbi.1004277. eCollection 2015 May.


The hydrophobic effect is the main driving force in protein folding. One can estimate the relative strength of this hydrophobic effect for each amino acid by mining a large set of experimentally determined protein structures. However, the hydrophobic force is known to be strongly temperature dependent. This temperature dependence is thought to explain the denaturation of proteins at low temperatures. Here we investigate if it is possible to extract this temperature dependence directly from a large set of protein structures determined at different temperatures. Using NMR structures filtered for sequence identity, we were able to extract hydrophobicity propensities for all amino acids at five different temperature ranges (spanning 265-340 K). These propensities show that the hydrophobicity becomes weaker at lower temperatures, in line with current theory. Alternatively, one can conclude that the temperature dependence of the hydrophobic effect has a measurable influence on protein structures. Moreover, this work provides a method for probing the individual temperature dependence of the different amino acid types, which is difficult to obtain by direct experiment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Amino Acids / chemistry*
  • Computational Biology
  • Crystallography, X-Ray
  • Databases, Protein
  • Hydrophobic and Hydrophilic Interactions
  • Magnetic Resonance Spectroscopy
  • Models, Statistical
  • Protein Denaturation
  • Protein Folding
  • Proteins / chemistry*
  • Solvents
  • Temperature
  • Water / chemistry


  • Amino Acids
  • Proteins
  • Solvents
  • Water

Grant support

SA has been supported by a Veni grant on the project ‘Understanding toxic protein oligomers through ensemble characteristics’ from Netherlands Organisation for Scientic Research (NWO)’. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.