pH-Induced Changes in Polypeptide Conformation: Force-Field Comparison with Experimental Validation.

Area of Science:

• Biophysics and Computational Chemistry
• Polymer Science and Engineering

Background:

• Charged polypeptides like poly l-lysine (PLL) and poly l-glutamic acid (PGA) are vital in surface modification and self-assembly.
• Understanding their pH-dependent structural and conformational changes is critical for controlling their properties.

Purpose of the Study:

• To investigate pH-induced changes in the secondary structure, charge, and conformation of PLL and PGA.
• To evaluate the performance of different molecular dynamics force fields in predicting these changes.

Main Methods:

• Combined experimental techniques: molecular dynamics (MD) simulations, circular dichroism, laser Doppler velocimetry, and dynamic light scattering.
• MD simulations utilized OPLS-AA, CHARMM27, and AMBER99SB*-ILDNP force fields to model peptide conformations.
• Analysis of secondary structure fractions and Ramachandran plots to assess force field accuracy.

Main Results:

• A narrow pH range was identified for stable colloidal suspensions of PLL and PGA, maintaining >60% α-helix content.
• Elevated charge promotes solvation as a random coil, while specific pH ranges support colloidal stability with α-helix structures.
• AMBER99SB*-ILDNP force field demonstrated the best agreement with experimental secondary structure distributions, particularly for pH-induced changes, though it overestimated α-helix content for fully charged PGA.

Conclusions:

• Significant deviations exist in current force fields' predictions for charged homopolypeptides.
• Fine-tuning pH is a critical, yet underappreciated, factor for controlling the secondary structure and colloidal stability of PLL and PGA.
• These findings have substantial implications for the practical application of charged homopolypeptides in surface modification and self-assembly.