The protein folding transition-state ensemble from a Gō-like model

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Characterizing transition states (TS) is crucial for understanding protein folding mechanisms.
• Experimental determination of TS is challenging, and protein engineering methods like phi-value analysis can be difficult to interpret.

Purpose of the Study:

• To theoretically investigate the nature of the transition state ensemble for three representative proteins across major structural classes.
• To elucidate the role of local and non-local contacts in protein folding transition states.

Main Methods:

• Utilized a mean-field C(α)-based Gō-model for theoretical simulations.
• Analyzed the structure of transition state ensembles in representative proteins.

Main Results:

• Transition state ensembles are dominated by local contacts.
• Non-local contacts predominantly form after crossing the macroscopic folding free energy barrier.
• The mean phi-value correlates with the fraction of stabilization energy at the barrier-top and depends on stability conditions.
• A connection exists between small destabilization, large phi-values, and residue location.

Conclusions:

• Local energetics play a critical role in determining protein folding mechanisms.
• Theoretical findings align with recent empirical observations in protein folding studies.