Structure change of β-hairpin induced by turn optimization: an enhanced sampling molecular dynamics simulation study

Area of Science:

• Protein folding dynamics
• Biophysics of protein structure
• Computational biochemistry

Background:

• Previous studies highlighted the role of turn conformational propensity in determining beta-hairpin folding free energy pathways.
• The specific turn sequence is crucial for the final stable structure of beta-hairpins.

Purpose of the Study:

• To investigate how turn conformational propensity affects the stable structure of beta-hairpins.
• To explore the impact of optimized turn sequences on GB1p peptide folding.
• To compare the folding pathways and structures of wild-type GB1p with its mutants.

Main Methods:

• Molecular dynamics simulations using integrated tempering sampling were employed.
• Simulations were performed on two GB1p peptide mutants (GB1m2 and GB1m3) with optimized turn sequences.
• Predicted stable structures were compared to wild-type GB1p and other mutants (GB1r1, GBr2).

Main Results:

• Turn optimization in GB1p generated a favored 5-residue type I(") turn, alongside the wild-type 6-residue type I turn.
• Two distinct hairpin structures emerged: a shifted asymmetric "misfolded" (M) state and a symmetric "folded" (F) state similar to wild-type.
• Optimized turns favored a shifted hairpin via a modified "zipping" model, while disfavored turns aligned with the "hydrophobic-core-centric" model.
• Moving the hydrophobic core away from the turn destabilized but did not alter the hairpin structure.

Conclusions:

• Turn conformational propensity is a key determinant of both folding pathways and stable structures in beta-hairpins.
• Turn optimization can induce significant changes in beta-hairpin structure by altering folding mechanisms.
• The interplay between turn propensity and hydrophobic core positioning influences hairpin stability and conformation.