Peptide Backbone Effect on Hydration Free Energies of Amino Acid Side Chains

We have studied the hydrophobicity of amino acid side chains by computing conditional solvation free energies that account for effects of the peptide backbone on the side chains’ solvent environment. The free energies reported herein correspond to a gas–liquid transfer process, which mimics solvation of the side chain under the condition that the backbone has been solvated already, and have been obtained on the basis of free energy calculations with empirical force field models. We find that the peptide backbone strongly impacts the solvation of nonpolar side chains, while its effect on the polar side chains is less pronounced. The results indicate that, in the presence of the short peptide backbone, nonpolar amino acid side chains are less hydrophobic than what is expected based on small molecule (analogue) solvation data

Solvation structures of sodium halides in dimethyl sulfoxide (DMSO)–methanol (MeOH) mixtures

<p>A constrained molecular dynamics technique has been used to study the structures and dynamics of the solvation shells of three sodium halides, namely sodium chloride (Na⁺–Cl⁻), sodium bromide (Na⁺–Br⁻) and sodium iodide (Na⁺–I⁻) in DMSO–MeOH mixtures. In the case of Na⁺–Cl⁻ and Na⁺–Br⁻, Na⁺ is preferentially solvated by DMSO and Cl⁻ and Br⁻ are preferentially solvated by methanol in the contact ion pair (CIP) state. In the solvent-assisted ion pair (SAIP) configuration, Na⁺ ions of Na⁺–Cl⁻ and Na⁺–Br⁻ are preferentially solvated by methanol and Cl⁻ and Br⁻ also show preferential solvation by methanol over DMSO. In the case of Na⁺–I⁻, the only preferential solvation is in the SAIP state for I⁻ ion by methanol. These observations are supported by the calculated excess coordination numbers and spatial density maps. The heights of the transition states barriers for CIPs and SAIPs/solvent-shared ion pairs (SSHIPs) are significantly affected when the mole fraction of methanol (x_MeOH) changes from 0.0 to 0.25 because of a significant increase in the methanol density around halides. From the analysis of angular distribution functions of DMSO and methanol around the cations and anions, it is seen that DMSO and methanol molecules are present in parallel dipolar orientations (with respect to cation–solvent vector) in the first coordination shell of these three ion pairs at the CIP and SAIP states. Methanol molecules are nearly in an antiparallel (with respect to ion–solvent vector) orientation around the three halide ions.</p

Impact of an Ionic Liquid on Amino Acid Side Chains: A Perspective from Molecular Simulation Studies

Ionic liquids (ILs) are known to modify the structural stability of proteins. The modification of the protein conformation is associated with the accumulation of ILs around the amino acid (AA) side chains and the nature of interactions between them. To understand the microscopic picture of the structural arrangements of ILs around the AA side chains, room temperature molecular dynamics (MD) simulations have been carried out in this work with a series of hydrophobic, polar and charged AAs in aqueous solutions containing the IL 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]) at 2 M concentration. The calculations revealed distinctly nonuniform distribution of the IL components around different AAs. In particular, it is demonstrated that the BMIM+ cations preferentially interact with the aromatic AAs through favorable stacking interactions between the cation imidazolium head groups and the aromatic AA side chains. This results in preferential parallel alignments and enhanced population of the cations around the aromatic AAs. The potential of mean force (PMF) calculations revealed that such favorable stacking interactions provide greater stability to the contact pairs (CPs) formed between the aromatic AAs and the IL cations as compared to the other AAs. It is further quantified that for most of the AAs (except the cationic ones), a favorable enthalpy contribution more than compensates for the entropy cost to form stable CPs with the IL cations. These findings are likely to provide valuable fundamental information toward understanding the effects of ILs on protein conformational stability

Molecular Simulation Study on Hofmeister Cations and the Aqueous Solubility of Benzene

We study the ion-specific salting-out process of benzene in aqueous alkali chloride solutions using Kirkwood–Buff (KB) theory of solutions and molecular dynamics simulations with different empirical force field models for the ions and benzene. Despite inaccuracies in the force fields, the simulations indicate that the decrease of the Setchenow salting-out coefficient for the series NaCl > KCl > RbCl > CsCl is determined by direct benzene–cation correlations, with the larger cations showing weak interactions with benzene. Although ion-specific aqueous solubilities of benzene may be affected by indirect ion–ion, ion–water, and water–water correlations, too, these correlations are found to be unimportant, with little to no effect on the Setchenow salting-out coefficients of the various salts. We further considered LiCl, which is experimentally known to be a weaker salting-out agent than NaCl and KCl and, therefore, ranks at an unusual position within the Hofmeister cation series. The simulations indicate that hydrated Li⁺ ions can take part of the benzene hydration shell while the other cations are repelled by it. This causes weaker Li⁺ exclusion around the solute and a resulting, weaker salting-out propensity of LiCl compared to that of the other salts. Removing benzene–water and benzene–salt electrostatic interactions in the simulations does not affect this mechanism, which may therefore also explain the smaller effect of LiCl, as compared to that of NaCl or KCl, on aqueous solvation and hydrophobic interaction of nonpolar molecules

Enthalpy–Entropy of Cation Association with the Acetate Anion in Water

Negatively charged carboxylate and phosphate groups on biomolecules have different affinity for Na⁺ and K⁺ ions. We performed molecular simulations and studied the pair potential of mean force between monovalent cations and the carboxylate group of the acetate anion in aqueous solution at 298 K. The simulations indicate that a larger affinity of Na⁺ over K⁺ in the contact ion pair (CIP) state is of entropic origin with the CIP state becoming increasingly populated at higher temperature. Differences between the osmotic activities of these two ions are however governed by interactions with acetate in the solvent-shared ion pair (SIP) state as was previously shown (Hess, B.; van der Vegt, N. F. A. <i>Proc. Natl. Acad. Sci. U.S.A.</i> <b>2009</b>, <i>106</i>, 13296). SIP states with Na⁺ are slightly more stable than SIP states with K⁺, resulting in a smaller osmotic activity of sodium. We discuss the different affinities of Na⁺ and K⁺ in the SIP state in terms of an enthalpy–entropy reinforcement mechanism which involves a water-mediated hydrogen-bonding interaction between the oppositely charged ions. SIP states are enthalpically favorable and become decreasingly populated at higher temperature

Correction to “Mutual Exclusion of Urea and Trimethylamine <i>N</i>‑Oxide from Amino Acids in Mixed Solvent Environment”

Correction to “Mutual Exclusion of Urea and Trimethylamine <i>N</i>‑Oxide from Amino Acids in Mixed Solvent Environment

Mutual Exclusion of Urea and Trimethylamine <i>N</i>‑Oxide from Amino Acids in Mixed Solvent Environment

We study the solvation of amino acids in pure-osmolyte and mixed-osmolyte urea and trimethylamine <i>N</i>-oxide (TMAO) solutions using molecular dynamics simulations. Analysis of Kirkwood–Buff integrals between the solution components provides evidence that in the mixed osmolytic solution, both urea and TMAO are mutually excluded from the amino acid surface, accompanied by an increase in osmolyte–osmolyte aggregation. Similar observations are made in simulations of a model protein backbone, represented by triglycine, and suggest that TMAO stabilizes proteins under urea denaturation conditions by effectively removing urea from the protein surface. The effects of the mixed osmolytes on the solvation of the amino acids and the backbone are found to be highly nonlinear in terms of the effects of the individual osmolytes and independent of differences in the strength of the TMAO–water interactions, as observed with different TMAO force fields