Specific Interactions of Sodium Salts with Alanine Dipeptide and Tetrapeptide in Water: Insights from Molecular Dynamics

Abstract

We examine computationally the dipeptide and tetrapeptide of alanine in pure water and solutions of sodium chloride (NaCl) and iodide (NaI), with salt concentrations up to 3 M. Enhanced sampling of the configuration space is achieved by the replica exchange method. In agreement with other works, we observe preferential sodium interactions with the peptide carbonyl groups, which are enhanced in the NaI solutions due to the increased affinity of the less hydrophilic iodide anion for the peptide methyl side-chains and terminal blocking groups. These interactions have been associated with a decrease in the helicities of more complex peptides. In our simulations, both salts have a small effect on the dipeptide, but consistently stabilize the intramolecular hydrogen-bonding interactions and "α-helical" conformations of the tetrapeptide. This behavior, and an analysis of the intermolecular interaction energies show that ion-peptide interactions, or changes in the peptide hydration due to salts, are not sufficient determining factors of the peptide conformational preferences. Additional simulations suggest that the observed stabilizing effect is not due to the employed force-field, and that it is maintained in short peptides but is reversed in longer peptides. Thus, the peptide conformational preferences are determined by an interplay of energetic and entropic factors, arising from the peptide sequence and length and the composition of the solution.

Effects of concentrated NaCl and KCl solutions on the behaviour of aqueous peptide bond environment: single-particle dynamics and H-bond structural relaxation

“…At very high concentrations, the formation of a contact ion pair contributes significantly, and the peak height will decrease. The similar nature of the interaction of cation with the carbonyl oxygen of NMA and anion-amide hydrogen were also found in previous studies of Ioannou et al [70], and the variations are more prominent at concentrated NaI solution comparable to NaCl solution in their study. The ion-water radial distribution functions are largely insensitive to salt concentration as shown in Figures 2(b) and 2(d) and 3(b) and 3(d) but higher peak height of these radial distribution functions indicates the stronger solvation shell of these ions at higher salt concentration.…”

“…Qualitatively, no appreciable difference is observed with non-polarisable force field. Ioannou et al [70] studied computationally the dipeptide and tetrapeptide of alanine in pure water and solutions of sodium chloride (NaCl) and sodium iodide (NaI). It was found that the preferential sodium interactions with the peptide carbonyl groups are enhanced in the NaI solutions due to the increased affinity of the less hydrophilic iodide anion for the peptide methyl side-chains and terminal blocking groups.…”

pH-Independence of Trialanine and the Effects of Termini Blocking in Short Peptides: A Combined Vibrational, NMR, UVCD, and Molecular Dynamics Study

“…AAA, the classical model system of unblocked tripeptides, essentially agrees in suggesting a large pPII content of its conformational distribution. 50, 73 On the contrary, the body of work on blocked dipeptides, particularly AdP, is voluminous, 29, 30, 32, 36, 37, 41-43 starting with the computational work of Ramachandran, Flory, and their coworkers who introduced this peptide as a model system for exhibiting random coil behavior. 18, 19 This view changed only when Han et al reported the results of DFT calculations on AdP in explicit water which clearly revealed a preference for pPII.…”

“…8, 13, 14, 18, 19, 28-40 Nearly fifty years after Ramachandran, Flory and co-workers used this peptide 18, 19 as a kind of canonical model system for describing the Ramachandran plot of residues in the unfolded state, numerous MD studies still use this peptide to explore the underlying physics of the pPII preference of alanine. 29, 30, 32, 36-38, 41, 42 Several experimental studies (IR, Raman, NMR) on this peptide have been carried out as well. 13, 15, 33-35, 43 Avbelj and coworkers reported propensity scales for all 19 non-proline residues in blocked dipeptides based on an analysis of the amide III region of their Raman and IR spectra.…”

“…As indicated above the assumed suitability of AdP as the simplest model system for studying peptide conformations has led to a flood of MD studies on this peptide in vacuo and in aqueous solution. 8, 29, 30, 32, 36-38, 40-43 One of the reasons for this multitude of studies is that MD simulations of unfolded peptides heavily depend on the choice of the force field. 53, 54 While earlier simulations with CHARMM and AMBER force fields led to an overemphasis of right-handed helical conformations, 21, 30, 54-56 more recent modified CHARMM and AMBER as well as OPLS force fields yielded a dominant population of the pPII/β conformations in the upper left quadrant of the Ramachandran plot.…”