Distinguishing between concerted, sequential and barrierless conformational changes: Folding versus allostery

Area of Science:

• Biochemistry
• Biophysics
• Structural Biology

Background:

• Characterizing transition and intermediate states of reactions is crucial for understanding reaction mechanisms.
• Linear free energy relationships (LFERs) are commonly used to study reaction mechanisms, particularly in protein folding.
• Application of LFERs to allosteric transitions is less explored, despite the importance of allosteric regulation in protein function.

Purpose of the Study:

• To draw analogies between the characterization of pathways and intermediates in protein folding and allosteric transitions.
• To highlight the potential of LFER analysis for studying allosteric mechanisms.
• To emphasize the importance of understanding allosteric switching mechanisms for protein function.

Main Methods:

• Conceptual analysis comparing methodologies used in protein folding and allosteric transition studies.
• Review of existing literature on LFER applications in different biological systems.
• Identification of shared principles in characterizing reaction intermediates and transition states.

Main Results:

• Analogies were identified in the approaches to characterize pathways and intermediates in both protein folding and allosteric transitions.
• LFER analysis, successful in folding studies, can be conceptually extended to allosteric transitions.
• Similarities exist in identifying and characterizing rate-limiting steps and transition states.

Conclusions:

• Characterizing transition states and intermediates using LFERs is a viable approach for understanding allosteric mechanisms.
• The principles applied to protein folding can inform the study of allosteric regulation.
• A deeper understanding of allosteric switching mechanisms is critical for deciphering protein function and for drug development.