Sampling the equilibrium kinetic network of Trp-cage in explicit solvent

Area of Science:

• Biophysics
• Computational Chemistry
• Protein Dynamics

Background:

• Understanding protein folding kinetics is crucial for deciphering biological function.
• The Trp-cage mini-protein serves as a model system for studying folding mechanisms.

Purpose of the Study:

• To elucidate the kinetic folding network of the Trp-cage mini-protein in explicit water.
• To identify and characterize metastable states and intermediates in the folding process.

Main Methods:

• Employed the single replica multiple state transition interface sampling (MSTIS) approach.
• Utilized cluster analysis to identify metastable states.
• Constructed a 14x14 kinetic rate matrix from simulation data.

Main Results:

• Identified 14 important metastable states in the kinetic network.
• Characterized a near-native intermediate state with a stable alpha helix, disordered proline tail, broken salt-bridge, and rotated arginine.
• Predicted rate constants and timescales consistent with experimental and previous simulation data.

Conclusions:

• The MSTIS approach successfully mapped the Trp-cage folding landscape.
• The identified near-native intermediate state provides insights into folding pathways and validates experimental observations.
• Computational simulations can accurately predict protein folding kinetics and intermediate structures.