Thermodynamic Modeling and Experimental Data Reveal That Sugars Stabilize Proteins According to an Excluded Volume Mechanism

J Am Chem Soc. 2023 Aug 2;145(30):16678-16690. doi: 10.1021/jacs.3c04293. Epub 2023 Jul 19.


We present a new thermodynamic model to investigate the relative effects of excluded volume and soft interaction contributions in determining whether a cosolute will either destabilize or stabilize a protein in solution. This model is unique in considering an atomistically detailed model of the protein and accounting for the preferential accumulation/exclusion of the osmolyte molecules from the protein surface. Importantly, we use molecular dynamics simulations and experiments to validate the model. The experimental approach presents a unique means of decoupling excluded volume and soft interaction contributions using a linear polymeric series of cosolutes with different numbers of glucose subunits, from 1 (glucose) to 8 (maltooctaose), as well as an 8-mer of glucose units in the closed form (γ-CD). By studying the stabilizing effect of cosolutes along this polymeric series using lysozyme as a model protein, we validate the thermodynamic model and show that sugars stabilize proteins according to an excluded volume mechanism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Glucose
  • Polymers
  • Proteins*
  • Sugars*
  • Thermodynamics


  • Sugars
  • Proteins
  • Polymers
  • Glucose