Metal-Ion Enhanced Helicity in the Gas Phase

Abstract

Recent studies have shown that protonated polyalanine peptides (Ala n +H) + are not helical in the gas phase, 1,2 despite alanine's high helix propensity in solution. 3 Here we show that substituting an alkali metal ion (Li + , Na + , K + , Rb + , or Cs + ) for the proton leads to a transformation from a random globule to a rigid helix. While metal ions have been found to enhance the helicity of small peptides in aqueous solution, [4][5][6][7][8] this often involves residues with high metal affinities locking in the helical conformation by formation of metal-mediated cross-links. The peptides discussed here do not have metal-complexing side chains. The enhanced helicity apparently results because the oxyphilic metal ions coordinate to CO groups at the C-terminus. This "caps" the helix 9,10 and allows favorable interactions between the metal ion and the helix dipole. [11][12][13] The interactions between metal ions and proteins play many important roles in energy metabolism and signaling. Metal ions often cause conformational changes when they bind to proteins, which can profoundly affect their properties. [14][15][16][17] Metal ion interactions also provide a valuable tool in the design of proteins. [18][19][20][21] There have been a number of experimental and theoretical studies of the interactions between small peptides and metal ions in the gas phase. These studies have focused on the energetics and location of metal binding, [22][23][24][25] on the conformations

Unraveling the Stability of Polypeptide Helices: Critical Role of van der Waals Interactions

“…By adding a charge near the C terminus (here we use Li þ , but the same conclusions hold for a simple positive point charge), the helix is significantly stabilized. This result agrees with the experimental observation that the helix formation requires charge capping the Ala n peptides near the C terminus [12][13][14]. We now turn to the role of vdW interactions for the relative stability of periodic polyalanine , , and 3 10 helices.…”

“…While the role of interactions underpinning helical stability (vdW, hydrogen bonding, and helix termination) has been established above, the missing ingredient to connect our calculations to real experimental systems [12][13][14][15] is including temperature effects. We first turn to the freeenergy hierarchy of different structure prototypes of Ac-Ala 15 -LysH þ .…”

“…Our study reveals the crucial role that van der Waals (vdW) interactions play for the helix stability and dynamics, illustrating how entropy is significantly altered as well. We choose polyalanine as a target for our study due to its high propensity to form helical structures [11], and its widespread use as a benchmark system for peptide stability in experiment [12][13][14][15] and in theory (see, e.g., Refs. [16][17][18][19][20][21][22][23][24] and references therein).…”

“…The charge capping at the C terminus is necessary to compensate the peptide macrodipole, and obtain stable helical structures in gas-phase experiments [12][13][14]. To quantify each contribution, we monitor the energy to add one amino acid residue to a finite polyalanine chain, E Ala ðnÞ ¼ E tot ðAla n Þ À E tot ðAla nÀ1 Þ, as a function of chain length n [20,21] in Fig.…”

Refinements to the Utah–Washington Mechanism of Electron Capture Dissociation

“…It is therefore useful to examine ECD data also from ref 50 on disulfide linked dimers (AcCA 10 -NH 2 +Na) 2 2+ similar to those whose ECD fragmentation patterns are shown in Figure 6 but with the C-termini amidated. Such ions are thought 65 to have Ala 10 α-helices with the Na + ions bound to the C-terminal −NH 2 sites. For such structures, the locations of the positive charges and the distances to various amide CO groups can more reliably be estimated because the charges do not reside on a flexible Lys side chain.…”