Polyelectrolyte Influence on Beta-Hairpin Peptide Stability: A Simulation Study.

Assemblies of proteins and charged macromolecules (polyelectrolytes) find important applications as pharmaceutical formulations, biocatalysts, and cell-contacting substrates. A key question is how the polymer component influences the structure and function of the protein. The present paper addresses the influence of charged polymers on the thermal stability of two model beta-hairpin-forming peptides through an all-atom, replica exchange molecular dynamics simulation. The (negatively charged) peptides consist of the terminal 16 amino acids of the B1 domain of Protein G (GB1) and a variant with three of the GB1 residues substituted with tryptophan (Tryptophan Zipper 4, or TZ4). A (cationic) lysine polymer is seen to thermally stabilize TZ4 and destabilize GB1, while a (also cationic) chitosan polymer slightly stabilizes GB1 but has essentially no effect on TZ4. Free energy profiles reveal folded and unfolded conformations to be separated by kinetic barriers generally acting in the direction of the thermodynamically favored state. Through application of an Ising-like statistical mechanical model, a mechanism is proposed based on competition between (indirect) entropic stabilization of folded versus unfolded states and (direct) competition for hydrogen-bonding and hydrophobic interactions. These findings have important implications to the design of polyelectrolyte-based materials for biomedical and biotechnological applications.