Free-Energy Analysis of Peptide Binding in Lipid Membrane Using All-Atom Molecular Dynamics Simulation Combined with Theory of Solutions

All-atom molecular dynamics (MD) simulations are performed to examine the stabilities of a variety of binding configurations of alamethicin, a 20-amino-acid amphipathic peptide, in the bilayers of 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) and 1,2-dimyristoyl-<i>sn</i>-glycero-3-phosphatidylcholine (DMPC). The binding free energy of alamethicin is calculated through a combination of MD simulation and the energy-representation theory of solutions, and it is seen that the transmembrane configuration is stable in both membranes. A surface-bound state is also found to be stable due to the balance between the attractive and repulsive interactions of the peptide with lipid and water, and the key role of water is pointed out for the stability in the interfacial region. A difference between the POPC and DMPC systems is noted when the polar C-terminal domain is buried in the hydrophobic region of the membrane. In POPC, the peptide is unfavorably located with that configuration due to the loss of electrostatic interaction between the peptide and lipid

Noncatalytic Hydrothermal Elimination of the Terminal d‑Glucose Unit from Malto- and Cello-Oligosaccharides through Transformation to d‑Fructose

Noncatalytic hydrothermolyses of malto- and cello-oligosaccharides (di-, tri-, tetraose), linked by α- and β-1,4-glycosidic bonds, respectively, were investigated at 100–140 °C. In situ ¹³C NMR spectroscopy was applied to elucidate the position and pathways of the glycosidic bond breakage and the dependence of the hydrolysis rate on the bond type. Spectral analysis was carried out quantitatively as a function of time with the mass balance confirmed, and it was shown for both the malto- and the cello-oligosaccharides that the terminal d-glucose unit with a free anomeric carbon is selectively eliminated after transformation to d-fructose. Site-selective breakage of the glycosidic bonds proceeded on the order of hours. The initial apparent rates for terminal hydrolysis were found to be independent of the degree of oligomerization but dependent on the type of glycosidic bond. Rate constants were larger for the α-1,4-linked malto-oligosaccharides by a factor of 3–4 than for the β-1,4-linked cello-oligosaccharides. The pathways and mechanisms for the malto- and cello-oligosaccharide hydrothermolyses are common and can be understood in terms of the elementary reactions of the di- and monosaccharides

Solvent Effect on Pathways and Mechanisms for d‑Fructose Conversion to 5‑Hydroxymethyl-2-furaldehyde: In Situ ¹³C NMR Study

Noncatalytic reactions of d-fructose were kinetically investigated in dimethylsulfoxide (DMSO), water, and methanol as a function of time at temperatures of 30–150 °C by applying in situ ¹³C NMR spectroscopy. The products were quantitatively analyzed with distinction of isomeric species by taking advantage of site-selective ¹³C labeling technique. In DMSO, d-fructose was converted first into 3,4-dihydroxy-2-dihydroxymethyl-5-hydroxymethyl­tetrahydrofuran having no double bond in the ring, subsequently into 4-hydroxy-5-hydroxymethyl-4,5-dihydrofuran-2-carbaldehyde having one double bond through dehydration, and finally into 5-hydroxymethyl-2-furaldehyde (5-HMF) having two double bonds. No other reaction pathways were involved, as shown from the carbon mass balance. In water, 5-HMF, the final product in DMSO, was generated with the precursors undetected and furthermore transformed predominantly into formic and levulinic acids and slightly into 1,2,4-benzenetriol accompanied by polymerization. d-Glucose was also produced through the reversible transformation of the reactant d-fructose. In methanol, some kinds of anhydro-d-fructoses were generated instead of 5-HMF. The reaction pathways can thus be controlled by taking advantage of the solvent effect. The d-fructose conversion reactions are of the first order with respect to the concentration of d-fructose and proceed on the order of minutes in DMSO but on the order of hours in water and methanol. The rate constant was three orders of magnitude larger in DMSO than in water or methanol

Energetic Analysis of Adsorption and Absorption of Small Molecule to Nanodroplet of Water

Adsorption and absorption were analyzed for nonpolar and polar solutes to a water droplet of nanometer size and to a planar slab. All-atom molecular dynamics simulation was performed, and the free energy change for bringing the solute to the water aggregate was computed over a wide range of temperature. It was seen in both the droplet and slab systems that the solute is preferably located at the surface, and the propensity of the nonpolar solute at the surface relative to the bulk was found to be larger in the droplet than in the slab. A molecular-sized curvature thus enhances the surface propensity of a nonpolar solute, whereas the curvature effect is weaker for polar one. The attractive and repulsive interactions of the solute with water were further analyzed, and the role of the repulsive interaction is discussed with respect to the stability of the surface-bound state

Spatial-Decomposition Analysis of Energetics of Ionic Hydration

Hydration energetics is analyzed for a set of ions. The analysis is conducted on the basis of a spatial-decomposition formula for the excess partial molar energy of the solute that expresses the thermodynamic quantity as an integral over the whole space of the solute–solvent and solvent–solvent interactions conditioned by the solute–solvent distance. It is observed for all the ionic solutes treated in the present work that the ion–water interaction is favorable at the expense of the water–water interaction and that the variations of the ion–water and water–water interactions with the ion–water distance compensate against each other beyond the contact distance. The extent of spatial localization of the excess partial molar energy is then assessed by introducing a cutoff into the integral expression and examining the convergence with respect to the change in the cutoff. It is found that the excess energy is not quantitatively localized within the first and second hydration layers, while its correlations over the variation of ions are good against the first-layer contribution

The Excess Chemical Potential of Water at the Interface with a Protein from End Point Simulations

We use end point simulations to estimate the excess chemical potential of water in the homogeneous liquid and at the interface with a protein in solution. When the pure liquid is taken as the reference, the excess chemical potential of interfacial water is the difference between the solvation free energy of a water molecule at the interface and in the bulk. Using the homogeneous liquid as an example, we show that the solvation free energy for growing a water molecule can be estimated by applying UWHAM to the simulation data generated from the initial and final states (i.e., “the end points”) instead of multistate free energy perturbation simulations because of the possible overlaps of the configurations sampled at the end points. Then end point simulations are used to estimate the solvation free energy of water at the interface with a protein in solution. The estimate of the solvation free energy at the interface from two simulations at the end points agrees with the benchmark using 32 states within a 95% confidence interval for most interfacial locations. The ability to accurately estimate the excess chemical potential of water from end point simulations facilitates the statistical thermodynamic analysis of diverse interfacial phenomena. Our focus is on analyzing the excess chemical potential of water at protein receptor binding sites with the goal of using this information to assist in the design of tight binding ligands

Comparative Study on the Properties of Hydration Water of Na- and K‑Halide Ions by Raman OH/OD-stretching Spectroscopy and Dielectric Relaxation Data

Properties of hypermobile water (HMW) were studied by Raman OH-stretching spectroscopy. Hydration water properties measured by Raman OH-stretching spectra of NaX/KX (X: Cl, Br, I) solutions (0.05–0.2 M) were comparatively analyzed with the data by dielectric relaxation spectroscopy (DRS), NMR, and statistical mechanical studies. The Raman OH-stretching spectra were well-fitted with linear combinations of the spectra of pure water both at the same and the higher temperatures. The fitting analysis determined the “structure temperature” <i>T</i>_str and mole fraction of the high <i>T</i>_str water region, giving the hydration number <i>N</i>_hyd, for each electrolyte solution. The determined <i>T</i>_str was much higher than the solution temperature of 293 K for each tested salt and was higher for larger halide ions, consistent with commonly known “structure-breaking” order Cl < Br < I. No significant differences in <i>N</i>_hyd were observed between NaX and KX and among even halide ion species within the experimental errors. Measured <i>N</i>_hyd values of 25–27 were much greater than the reported numbers by NMR chemical shift and ¹⁷O NMR relaxation studies and comparable to the numbers of hypermobile water reported in the previous DRS studies. The results indicated that the hydration region around NaX or KX measured by the present Raman study was nearly overlapped with the region of HMW by DRS. It was also suggested that differences in the ion size effects on <i>T</i>_str and the DR frequency resulted from the sensitivity difference to long-range many-body interactions among water molecules. High structure–temperature regions were also detected by the analysis of OH-stretching and OD-stretching bands for 0.2 M NaI in H₂O/D₂O mixed solvent of 50 mol %, and we found that both OH-stretching and OD-stretching bands have almost equivalent <i>T</i>_str ≈ 330 K and mole fractions with each other

Anion-Dependence of Fast Relaxation Component in Na‑, K‑Halide Solutions at Low Concentrations Measured by High-Resolution Microwave Dielectric Spectroscopy

High-resolution microwave dielectric spectra of NaX, KX (X: F, Cl, Br, I) aqueous solutions of <i>c</i> = 0.05 and 0.1 M measured in the frequency range 0.2–26 GHz at 10 °C are analyzed. The dielectric relaxation (DR) spectrum of each solution, which deviates slightly from the bulk-water spectrum, is mathematically divided into the bulk-water spectrum and the spectrum of solute particles covered with a water layer using a mixture theory by assuming the existence of continuous bulk-water phase. The solute spectra above 3 GHz are fitted with a linear series of pure water component (γ dispersion with DR frequency <i>f</i>_w), fast Debye component–1 with DR frequency <i>f</i>₁ (><i>f</i>_w), and slow Debye component–2 with DR frequency <i>f</i>₂ (<<i>f</i>_w). Component–2 is only found for the fluorides. The sum of dispersion amplitudes of γ and components −1 and −2 for NaX and KX are found to be almost irrespective of X and equal to the pure water level, indicating that components −1 and −2 are from the water modified by ions, thus denoted as “hypermobile water” and “constrained water” (not rigidly bound to ion), respectively. Below 3 GHz, sub-GHz dispersion component is detected and assigned as a relaxation response of counterion cloud. The resulting limiting-molar conductivities of NaX and KX are in good agreement with the literature data measured at much lower frequencies. The estimated number of hypermobile water molecules is found to increase from 9 to 31 for NaX and from 9 to 37 for KX with increasing anion size. Thus, except for the fluorides, it is reported that the modified water by salt ions exhibits only Debye component–1 other than γ dispersion, indicating the existence of a water–ions collective hypermobile mode in each solution

Drastic Compensation of Electronic and Solvation Effects on ATP Hydrolysis Revealed through Large-Scale QM/MM Simulations Combined with a Theory of Solutions

Hydrolysis of adenosine triphosphate (ATP) is the “energy source” for a variety of biochemical processes. In the present work, we address key features of ATP hydrolysis: the relatively moderate value (about −10 kcal/mol) of the standard free energy, Δ<i>G</i>_hyd, of reaction and the insensitivity of Δ<i>G</i>_hyd to the number of excess electrons on ATP. We conducted quantum mechanical/molecular mechanical simulation combined with the energy-representation theory of solutions to analyze the electronic-state and solvation contributions to Δ<i>G</i>_hyd. It was revealed that the electronic-state contribution in Δ<i>G</i>_hyd is largely negative (favorable) upon hydrolysis, due to the reduction of electrostatic repulsion accompanying the breakage of the P–O bond. In contrast, the solvation effect was found to be strongly more favorable on the reactant side. Thus, we showed that a drastic compensation of the two opposite effects takes place, leading to the modest value of Δ<i>G</i>_hyd at each number of excess electrons examined. The computational analyses were also conducted for pyrophosphate ions (PPi), and the parallelism between the ATP and PPi hydrolyses was confirmed. Classical molecular dynamics simulation was further carried out to discuss the effect of the solvent environment; the insensitivity of Δ<i>G</i>_hyd to the number of excess electrons was seen to hold in solvent water and ethanol