Conformations of Unsolvated Valine-Based Peptides

Abstract

High-resolution ion mobility measurements and molecular dynamics (MD) simulations have been used to study the conformations of unsolvated valine-based peptides with up to 20 residues. In aqueous solution, valine is known to have a high propensity to form β-sheets and a low propensity to form α-helices. A variety of protonated valine-based peptides were examined in vacuo: Val n +H+, Ac-Val n -Lys+H+, Ac-Lys-Val n +H+, Val n -Gly-Gly-Val m +H+, Val n -LPro-Gly-Val m +H+, Val n -DPro-Gly-Val m +H+, Ac-Val n -Gly-Lys-Val m +H+, Ac-Val n +H+, and Arg-Val n +H+. Peptides designed to be β-hairpins were found to be random globules or helices. The β-hairpin is apparently not favored for valine-based peptides in vacuo, which is in agreement with the predictions of MD simulations. Peptides designed to be α-helices appear to be partial α/partial π-helices. Insertion of Gly-Gly, LPro-Gly, or DPro-Gly into the center of a polyvaline peptide disrupts helix formation. Some of the peptides that were expected to be random globules (because their most basic protonation site is near the N-terminus where protonation destabilizes the helix) were found to be helical with the proton located near the C-terminus. Helix formation appears to be more favorable in unsolvated valine-based peptides than in their alanine analogues. This is the reverse of what is observed in aqueous solution, but appears to parallel the helix propensities determined in polar solvents.

Ion Mobility Measurements of Nondenatured 12–150 kDa Proteins and Protein Multimers by Tandem Differential Mobility Analysis–Mass Spectrometry (DMA-MS)

“…First, it has a firm experimental basis for globular shapes, covering all the relevant protein size range. Second, although the EHSS model has demonstrated great utility in the case of small clusters of reasonably well-known structure [59][60][61], its empirical support is much weaker for proteins whose gas structure is not firmly known, and most often differs from the crystal structure (even for protein ions electrosprayed from neutral aqueous solutions) [4]. Finally, EHSS calculations become increasingly difficult at large protein masses, and would be even harder in molecular gases and with the largest ions used here.…”

Folding and unfolding of helix-turn-helix motifs in the gas phase

“…Average collision cross sections were calculated for conformations derived from the MD simulations using the empirically corrected exact hard sphere scattering approximation [18,19], which correctly accounts for multiple scattering effects. Average cross sections were obtained by taking 50 snapshots from the last 35 ps of the MD simulation.…”

Binding energies of water to lithiated valine: Formation of solution-phase structure in vacuo

“…Studies of gas-phase peptides indicate that ␣-helices can be stable in the absence of water and indicate that the propensity for helix formation for some amino acids differs in the gas phase and in solution [1,2]. For example, peptides with high valine content have a higher helix-forming propensity than their alanine analogues in the gas phase, but just the opposite is observed in aqueous solution [1].In the condensed phase, specific water molecules can play an important role in molecular structure. Such specific water molecules are often observed in crystal structures of proteins and other molecules.…”