Modelling of pH-dependence to develop a strategy for stabilising mAbs at acidic steps in production

Max Hebditch, Ryan Kean, James Warwicker

Research output: Contribution to journalArticlepeer-review


Engineered proteins are increasingly being required to function or pass through environmental stresses for which the underlying protein has not evolved. A major example in health are antibody therapeutics, where a low pH step is used for purification and viral inactivation. In order to develop a computational model for analysis of pH-stability, predictions are compared with experimental data for the relative pH-sensitivities of antibody domains. The model is then applied to proteases that have evolved to be functional in an acid environment, showing a clear signature for low pH-dependence of stability in the neutral to acidic pH region, largely through reduction of salt-bridges. Interestingly, an extensively acidic protein surface can maintain contribution to structural stabilisation at acidic pH through replacement of basic sidechains with polar, hydrogen-bonding groups. These observations form a design principle for engineering acid-stable proteins.
Original languageEnglish
Pages (from-to)897-905
JournalComputational and Structural Biotechnology Journal
Early online date10 Mar 2020
Publication statusPublished - 16 Apr 2020


  • Biophysics
  • Biopharmaceuticals
  • Antibodies
  • Purification
  • Acid-stability
  • Electrostatics


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