Ion-specificity in {\alpha}-helical folding kinetics

TL;DR

This study uses molecular dynamics simulations to show how different salts, especially sodium salts, significantly slow down alpha-helical folding by forming long-lived ion-peptide interactions, affecting folding kinetics and energy landscapes.

Contribution

It reveals the ion-specific effects on peptide folding kinetics and elucidates the molecular mechanisms behind salt-induced kinetic barriers and configurational mobility changes.

Findings

Sodium salts increase folding times by about tenfold.

Long-lived sodium ion binding causes non-exponential residence times.

Salt modifies energy landscapes and reduces peptide diffusivity.

Abstract

The influence of the salts KCl, NaCl, and NaI at molar concentrations on the {\alpha}-helical folding kinetics of the alanine-based oligopeptide Ace-AEAAAKEAAAKA-Nme is investigated by means of (explicit-water) molecular dynamics simulations and a diffusional analysis. The mean first passage times for folding and unfolding are found to be highly salt-specific. In particular, the folding times increase about one order of magnitude for the sodium salts. The drastic slowing down can be traced back to long-lived, compact configurations of the partially folded peptide, in which sodium ions are tightly bound by several carbonyl and carboxylate groups. This multiple trapping is found to lead to a non-exponential residence time distribution of the cations in the first solvation shell of the peptide. The analysis of {\alpha}-helical folding in the framework of diffusion in a reduced (one-dimensional) free energy landscape further shows that the salt not only specifically modifies equilibrium properties, but also induces kinetic barriers due to individual ion binding. In the sodium salts, for instance, the peptide's configurational mobility (or "diffusivity") can decrease about one order of magnitude. This study demonstrates the highly specific action of ions and highlights the intimate coupling of intramolecular friction and solvent effects in protein folding.