Kinetics of Loop Closure in Disordered Proteins: Theory vs Simulations vs Experiments

Area of Science:

• Protein dynamics
• Biophysics
• Computational biology

Background:

• Intrinsically disordered proteins (IDPs) lack stable tertiary structures.
• Understanding their intrachain dynamics, like loop formation, is crucial.
• Existing models struggle to fully capture IDP behavior.

Purpose of the Study:

• To investigate the time scales of loop formation in intrinsically disordered proteins.
• To compare different theoretical models with simulation and experimental data.
• To identify the most accurate models for describing protein loop dynamics.

Main Methods:

• Atomistic simulations of protein dynamics.
• Experiment-parametrized coarse-grained models.
• One-dimensional theories (Markovian and non-Markovian dynamics).

Main Results:

• A simple 1D diffusion model accurately predicts mean first passage times for loop closure.
• This 1D model aligns with coarse-grained, atomistic simulations, and experimental data.
• Longer chains exhibit non-Markovian effects, better described by generalized Langevin equation at intermediate times.
• Atomistic simulations reveal long tails in transition path times at long times, deviating from simpler models.

Conclusions:

• The 1D diffusion model is a valid tool for interpreting experimental data on protein loop formation.
• Non-Markovian effects become significant in longer polypeptide chains.
• Advanced models like the generalized Langevin equation are needed for intermediate timescales.
• Discrepancies at long timescales highlight limitations of current models and suggest further research directions.