Thermodynamics and folding pathways of trpzip2: an accelerated molecular dynamics simulation study

Area of Science:

• Computational Biology
• Biophysics
• Protein Folding Dynamics

Background:

• Understanding protein folding mechanisms is crucial for molecular biology and drug discovery.
• Beta-hairpins, like trpzip2, are small protein motifs that serve as model systems for studying folding.
• Accurate simulation of protein folding requires efficient sampling methods and reliable force fields.

Purpose of the Study:

• To investigate the folding mechanism and pathways of the beta-hairpin trpzip2.
• To utilize an enhanced sampling method for efficient simulation of protein folding and unfolding events.
• To determine the folding landscape and thermodynamics of trpzip2.

Main Methods:

• Application of an enhanced sampling method with an all-atom protein potential and implicit solvent model.
• Generation of multiple folding and unfolding trajectories for trpzip2.
• Estimation of the diffusion constant using explicit solvent and application of Kramer's theory.

Main Results:

• Identification of a two-stage folding process for trpzip2: hydrophobic collapse followed by hydrogen bond formation.
• Characterization of a transition state with one native hydrogen bond, supporting a 'zip-out' folding mechanism.
• Calculation of the folding rate using free energy profiles and diffusion constants, yielding a folding time consistent with experimental data.

Conclusions:

• The enhanced sampling method provides sufficient sampling for detailed analysis of protein folding landscapes.
• The folding mechanism of trpzip2 is characterized by an initial collapse and subsequent hydrogen bond formation.
• Computational predictions of folding rates can be validated against experimental measurements.