A literature review of the effects of small molecules on the stability of proteins Thermodynamics of protein folding & stability Proteins have the unique ability to spontaneously form a highly ordered, asymmetric and aperiodic three-dimensional conformation, known as the native structure, which is necessary to carry out their unique functions in the cell. This capacity to repeatedly form a specific structure was initially linked to a thermodynamic hypothesis by Anfinsen (Anfinsen 1973). He discovered that the native structure was the protein conformation with the lowest Gibbs free energy under normal physiological conditions i.e. the most thermodynamically favourable. He also found with experiments involving denatured ribonuclease that, under the right conditions, the protein would be “unscrambled” or refolded, which demonstrated the reversibility of protein unfolding, further supporting the thermodynamic hypothesis. Proteins are only marginally stable in their native form due to the very small change in free energy (ΔG) between the denatured and the native state – around -5.15 kcal for most naturally occurring proteins (Pace 1990). The change in enthalpy (ΔH) is highly negative due to hydrogen bond formation during folding, which favours the native state. Although there is a negative, and so favourable, change in entropy (-TΔS) associated with desolvation of the apolar core upon folding, there is also a positive, and so unfavourable, change in entropy (-TΔS) of the protein structure, which results in
A literature review of the effects of small molecules on the stability of proteins Thermodynamics of protein folding & stability Proteins have the unique ability to spontaneously form a highly ordered, asymmetric and aperiodic three-dimensional conformation, known as the native structure, which is necessary to carry out their unique functions in the cell. This capacity to repeatedly form a specific structure was initially linked to a thermodynamic hypothesis by Anfinsen (Anfinsen 1973). He discovered that the native structure was the protein conformation with the lowest Gibbs free energy under normal physiological conditions i.e. the most thermodynamically favourable. He also found with experiments involving denatured ribonuclease that, under the right conditions, the protein would be “unscrambled” or refolded, which demonstrated the reversibility of protein unfolding, further supporting the thermodynamic hypothesis. Proteins are only marginally stable in their native form due to the very small change in free energy (ΔG) between the denatured and the native state – around -5.15 kcal for most naturally occurring proteins (Pace 1990). The change in enthalpy (ΔH) is highly negative due to hydrogen bond formation during folding, which favours the native state. Although there is a negative, and so favourable, change in entropy (-TΔS) associated with desolvation of the apolar core upon folding, there is also a positive, and so unfavourable, change in entropy (-TΔS) of the protein structure, which results in