Salt-specific stability and denaturation of a short salt-bridge forming alpha-helix

TL;DR

This study uses molecular dynamics simulations to explore how different salts affect the stability and denaturation of a short alpha-helix peptide, revealing salt-specific mechanisms involving ion binding and hydration effects.

Contribution

It provides detailed molecular insights into salt-specific effects on peptide stability, highlighting the roles of ion affinity and hydration in denaturation mechanisms.

Findings

NaCl destabilizes the peptide, consistent with experiments.

NaI is a stronger denaturant than NaCl.

K+ salts have minimal impact on stability.

Abstract

The structure of a single alanine-based Ace-AEAAAKEAAAKA-Nme peptide in explicit aqueous electrolyte solutions (NaCl, KCl, NaI, and KF) at large salt concentrations (3-4 M) is investigated using 1 microsecond molecular dynamics (MD) computer simulations. The peptide displays 71 alpha-helical structure without salt and destabilizes with the addition of NaCl in agreement with experiments of a somewhat longer version. It is mainly stabilized by direct and indirect (i+4)EK salt bridges between the Lys and Glu side chains and a concomitant backbone shielding mechanism. NaI is found to be a stronger denaturant than NaCl, while the potassium salts hardly show influence. Investigation of the molecular structures reveals that consistent with recent experiments Na+ has a much stronger affinity to side chain carboxylates and backbone carbonyls than K+, thereby weakening salt bridges and secondary structure hydrogen bonds. At the same time the large I- has a considerable affinity to the nonpolar alanine in line with recent observations of a large propensity of I- to adsorb to simple hydrophobes, and thereby 'assists' Na+ in its destabilizing action. In the denatured states of the peptide novel long-lived (10-20 ns) 'loop'-configurations are observed in which single Na+ ions and water molecules are hydrogen-bonded to multiple backbone carbonyls. In an attempt to analyze the denaturation behavior within the preferential interaction formalism, we find indeed that for the strongest denaturant, NaI, the protein is least hydrated. Additionally, a possible indication for protein denaturation might be a preferential solvation of the first solvation shell of the peptide backbone by the destabilizing cosolute (sodium).