What is the time scale for α-helix nucleation?

Area of Science:

• Protein dynamics
• Biophysical chemistry
• Computational biology

Background:

• Helix formation is crucial for protein folding, yet its kinetics are complex and not fully understood.
• Ultrafast spectroscopy suggested faster helix nucleation than previously thought for Ac-WAAAH(+)-NH(2).

Purpose of the Study:

• To investigate the kinetics of helix formation in the peptide Ac-WAAAH(+)-NH(2) using molecular dynamics simulations.
• To reconcile experimental observations with theoretical models of helix formation.

Main Methods:

• Replica-exchange molecular dynamics simulations with Amber ff03w force field and TIP4P/2005 water model.
• Calculation of temperature-dependent microscopic rate coefficients using a Markov process formalism.
• Simulated temperature jumps to generate fluorescence relaxation curves.

Main Results:

• Simulated relaxation curves closely matched experimental data, showing multiphasic kinetics approximated by a double-exponential function.
• Major relaxation processes identified as C-terminal helical state shrinking and coil state re-equilibration.
• Estimated helix nucleation time at 300 K is 20-70 ns, consistent with Arrhenius kinetics.

Conclusions:

• Molecular dynamics simulations accurately capture helix formation kinetics, including fast relaxation and slow nucleation.
• The study provides a detailed mechanistic insight into peptide helix formation.
• Discrepancy between observed fast relaxation and slow nucleation is explained by dominant coil dynamics.