Backbone flexibility and stability of reverse turn conformation in a model system

Area of Science:

• Computational chemistry
• Biophysics
• Molecular modeling

Background:

• Peptides containing cysteine residues can form disulfide bridges, influencing their three-dimensional structure.
• Turn conformations are crucial structural motifs in proteins, impacting their function.
• Understanding peptide conformational preferences is key to designing novel biomolecules.

Purpose of the Study:

• To investigate the conformational preferences of peptides with the sequence Ac-Cys-Pro-Xaa-Cys-NMe using molecular dynamics simulations.
• To compare simulation results with experimental free energy differences for disulfide-bridged turn formation.
• To analyze the stability of different turn conformations (Type I and Type II) for varying Xaa residues (Aib, Gly, Val).

Main Methods:

• Molecular dynamics (MD) simulations were employed to study peptide conformations.
• Free energy differences (delta delta G degree) were calculated to quantify conformational stability.
• The impact of a reduced 1-4 non-bonded interaction potential was evaluated.

Main Results:

• MD simulations successfully reproduced experimental differences in propensity for disulfide-bridged turn formation within 2 kJ/mol.
• The stability of Type I and Type II turns varied depending on the Xaa residue: Aib peptides showed similar stability, Val peptides favored Type I, and Gly peptides favored Type II.
• Simulations revealed differences in backbone conformations for the valine peptide between solution and crystal states.
• A reduced interaction potential showed slightly poorer agreement with experimental data.

Conclusions:

• Intramolecular hydrogen bonding stabilizes turn conformations with psi i+2 near 0 in confined environments, similar to protein structures.
• In solution, interactions with water stabilize alternative conformations with different psi i+2 values, resembling isolated residue minima.