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Keywords:

  • protein aggregation;
  • amyloid beta protein;
  • solvation free energy;
  • molecular dynamics simulation;
  • integral-equation theory

Hydrophobicity of a protein is considered to be one of the major intrinsic factors dictating the protein aggregation propensity. Understanding how protein hydrophobicity is determined is, therefore, of central importance in preventing protein aggregation diseases and in the biotechnological production of human therapeutics. Traditionally, protein hydrophobicity is estimated based on hydrophobicity scales determined for individual free amino acids, assuming that those scales are unaltered when amino acids are embedded in a protein. Here, we investigate how the hydrophobicity of constituent amino acid residues depends on the protein context. To this end, we analyze the hydration free energy—free energy change on hydration quantifying the hydrophobicity—of the wild-type and 21 mutants of amyloid-beta protein associated with Alzheimer's disease by performing molecular dynamics simulations and integral-equation calculations. From detailed analysis of mutation effects on the protein hydrophobicity, we elucidate how the protein global factor such as the total charge as well as underlying protein conformations influence the hydrophobicity of amino acid residues. Our results provide a unique insight into the protein hydrophobicity for rationalizing and predicting the protein aggregation propensity on mutation, and open a new avenue to design aggregation-resistant proteins as biotherapeutics. © 2014 Wiley Periodicals, Inc.