Selection for cooperativity causes epistasis predominately between native contacts and enables epistasis-based...

Area of Science:

• Protein folding and evolution
• Biophysics
• Computational biology

Background:

• Epistasis and cooperativity arise from protein energetic interactions.
• The relationship between epistasis and cooperativity, especially under selection, is not well understood.

Purpose of the Study:

• To investigate the relationship between epistasis and cooperativity under different selective pressures.
• To determine how selection for each property influences the other and its implications for protein structure prediction.

Main Methods:

• Simulated protein evolution under selection for cooperativity.
• Simulated protein evolution under selection for epistasis.
• Evaluated the impact on native and nonnative contact epistasis and overall cooperativity.
• Modeled the evolution of guanine nucleotide-binding protein (GB1) with and without cooperativity.

Main Results:

• Selection for cooperativity increased epistasis in native contacts but decreased it in nonnative contacts.
• Selection for epistasis enhanced interactions in both native and nonnative contacts while reducing cooperativity.
• Epistasis effectively mapped the native GB1 structure when cooperativity was present.
• Stable intermediate states (low cooperativity) obscured the native structure when reconstructing it via epistasis.

Conclusions:

• Selection for cooperativity is crucial for utilizing epistasis to predict protein structure.
• Reconstructing protein structure using epistasis measurements may be unreliable for proteins with stable intermediate states.