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The asymmetric solvation of ions can be defined as the tendency of a solvent to preferentially solvate anions over cations or cations over anions, at identical ionic charge magnitudes and effective sizes. Taking water as a reference, these effects are quantified experimentally for many solvents by the relative acity (A) and basity (B) parameters of the Swain scale. The goal of the present study is to investigate the asymmetric solvation of ions using molecular dynamics simulations, and to connect the results to this empirical scale. To this purpose, the charging free energies of alkali and halide ions, and of their hypothetical oppositely charged counterparts, are calculated in a variety of solvents. In a first set of calculations, artificial solvent models are considered that present either a charge or a shape asymmetry at the molecular level. The solvation asymmetry, probed by the difference in charging free energy between the two oppositely charged ions, is found to encompass a term quadratic in the ion charge, related to the different solvation structures around the anion and cation, and a term linear in the ion charge, related to the solvation structure around the uncharged ion-sized cavity. For these simple solvent models, the two terms are systematically counteracting each other, and it is argued that only the quadratic term should be retained when comparing the results of simulations involving physical solvents to experimental data. In a second set of calculations, 16 physical solvents are considered. The theoretical estimates for the acity A are found to correlate very well with the Swain parameters, whereas the correlation for B is very poor. Based on this observation, the Swain scale is reformulated into a new scale involving an asymmetry parameter Σ, positive for acitic solvents and negative for basitic ones, and a polarity parameter Π. This revised scale has the same predictive power as the original scale, but it characterizes asymmetry in an absolute sense, the atomistic simulations playing the role of an extra-thermodynamic assumption, and is optimally compatible with the simulation results. Considering the 55 solvents in the Swain set, it is observed that a moderate basity (Σ between −0.9 and −0.3, related to electronic polarization) represents the baseline for most solvents, while a highly variable acity (Σ between 0.0 and 3.0, related to hydrogen-bond donor capacity modulated by inductive effects) represents a landmark of protic solvents. [ABSTRACT FROM AUTHOR]

The calculation of the relative free energies of ligand-protein binding, of solvation for different compounds, and of different conformational states of a polypeptide is of considerable interest in the design or selection of potential enzyme inhibitors. Since such processes in aqueous solution generally comprise energetic and entropic contributions from many molecular configurations, adequate sampling of the relevant parts of configurational space is required and can be achieved through molecular dynamics simulations. Various techniques to obtain converged ensemble averages and their implementation in the GROMOS software for biomolecular simulation are discussed, and examples of their application to biomolecules in aqueous solution are given., (© 2011 American Chemical Society)

Eight 100-ns molecular dynamics simulations of a beta-heptapeptide in methanol at 340 K (within cubic periodic computational boxes of about 6-nm edge) are reported and compared. These simulations were performed with three different charge-state combinations at the peptide termini, one of them with or without a neutralizing chloride counterion, and using either the lattice-sum (LS) or reaction-field (RF) scheme to handle electrostatic interactions. The choice of the electrostatic scheme has essentially no influence on the folding-unfolding equilibrium when the peptide termini are uncharged and only a small influence when the peptide is positively charged at its N-terminus (with or without inclusion of a neutralizing chloride counterion). However, when the peptide is zwitterionic, the LS scheme leads to preferential sampling of the high-dipole folded helical state, whereas the RF scheme leads to preferential sampling of a low-dipole unfolded salt-bridged state. A continuum electrostatics analysis based on the sampled configurations (zwitterionic case) suggests that the LS scheme stabilizes the helical state through artificial periodicity, but that the magnitude of this perturbation is essentially negligible (compared to the thermal energy) for the large box size and relatively polar solvent considered. The results thus provide clear evidence (continuum electrostatics analysis) for the absence of LS artifacts and some indications (still not definitive because of the limited sampling of the folding-unfolding transition) for the presence of RF artifacts in this specific system.

Molecular dynamics simulations are used to investigate the interaction of the sugars trehalose, maltose, and glucose with a phospholipid bilayer at atomic resolution. Simulations of the bilayer in the absence or in the presence of sugar (2 molal concentration for the disaccharides, 4 molal for the monosaccharide) are carried out at 325 and 475 K. At 325 K, the three sugars are found to interact directly with the lipid headgroups through hydrogen bonds, replacing water at about one-fifth to one-quarter of the hydrogen-bonding sites provided by the membrane. Because of its small size and of the reduced topological constraints imposed on the hydroxyl group locations and orientations, glucose interacts more tightly (at identical effective hydroxyl group concentration) with the lipid headgroups when compared to the disaccharides. At high temperature, the three sugars are able to prevent the thermal disruption of the bilayer. This protective effect is correlated with a significant increase in the number of sugar-headgroups hydrogen bonds. For the disaccharides, this change is predominantly due to an increase in the number of sugar molecules bridging three or more lipid molecules. For glucose, it is primarily due to an increase in the number of sugar molecules bound to one or bridging two lipid molecules.

Single-chain and single-fragment configurational entropies of lipid tails in hydrated lipid bilayers are evaluated from molecular dynamics simulations using the quasi-harmonic approximation. The entropy distribution along individual acyl tails is obtained and compared to that of corresponding hydrocarbon chains in the liquid phase. We consider pure dipalmitoylphosphatidylcholine and mixed dioleoylphosphatidylcholine/dioleoylphosphatidylethanolamine bilayers. The systems are modeled at different levels of spatial resolution: In an atomic-level (AL) model all (heavy) atoms are explicitly simulated; in a coarse-grained (CG) model particles (beads) representing groups of covalently bound atoms are used, which map approximately four non-hydrogen atoms to one interaction site. Single-chain and single-fragment entropies and correlations between the motions of (single) acyl chains are compared. A good correspondence is found between the flexibility of the AL and CG models. The loss in configurational entropy due to the reduction in the number of degrees of freedom upon coarse-graining of the model is estimated. The CG model shows about 4 times faster convergence of the chain entropies than the more detailed AL model. Corrections to the quasi-harmonic entropy estimates were found to be small for the CG model. For the AL model, the correction due to mode anharmonicities is small, but the correction due to pairwise (supralinear) mode correlations is sizable.

This article investigates the convergence of structural and dynamical properties with system size and with time in molecular dynamics simulations of solvated phospholipid bilayers performed at constant volume under periodic boundary conditions using lattice-sum electrostatics. The electron density profile across the bilayer, the carbon-deuterium order parameters, and the surface tension are shown to be converged for a bilayer containing 36 lipids per leaflet and simulated over a period of 3-4 ns. Reasonable estimates for these properties can already be obtained from a system containing 16 lipids per leaflet. The convergence limit of 36 lipids per leaflet and the investigation of the correlation between lipid headgroup dipoles suggest a correlation length of about 3-5 nm in the lateral directions for a hydrated DPPC bilayer in the liquid-crystalline phase. Although these (relatively small) system sizes and (relatively short) time scales appear sufficient to obtain converged collective structural properties at constant volume, two restrictions should be kept in mind: (i) the relaxation times associated with the motion of individual lipids may be much longer and (ii) simulated properties converge significantly faster under constant volume conditions as compared to constant pressure conditions. Therefore, an accurate assessment of the dynamical properties of the system or of the relaxation of the bilayer under constant pressure conditions may require longer simulation time scales.