Solvent-separated Configurations Research Articles

Mechanistic Insights into Polyphenols' Aggregation Inhibition of α-Synuclein and Related Peptides.

While several polyphenols were found to either inhibit or modulate the aggregation of proteins implicated in neurodegenerative diseases, such as Parkinson's disease (PD), discrepant action mechanisms have been reported. This, in addition to some polyphenols' pan-assay interference compounds' reputation, casts some doubts concerning their therapeutic relevance. Here, we studied, through molecular dynamics and enhanced sampling methods, the aggregation of 11-mer peptides from the non-amyloid-β component, an aggregation-prone domain of α-synuclein (α-syn) implicated in PD and other synucleinopathies, in neat water and aqueous solutions of resveratrol (RSV) and gallic acid (GA). Further, simulations of the complete protein were carried out in aqueous urea, RSV, and GA solutions. Our results show that peptide aggregation is not disrupted by either phenolic compound. Thus, instead, intrusion of RSV and GA in the inter-peptide region induces a peptide-peptide re-orientation, favoring terminal interactions that manifest in the formation of barrierless solvent-separated configurations. Moreover, although the (poly)phenols induce a pronounced peptide dewetting at high concentrations, β-sheet-rich regions, a hallmark of α-syn aggregation, are not disrupted. Thus, our results indicate that, if anything, RSV and GA delay or modulate peptide aggregation at high concentrations via the stabilization of solvent-separated conformations as opposed to aggregation inhibition. Structural analysis of the full protein, however, shows that the (poly)phenols induce more extended conformations of α-syn, similar to urea, possibly also influencing its aggregation propensity. However, opposite to urea, the (poly)phenols reduce α-syn's conformational space, likely due to steric effects and a slowdown of the solvent dynamics. These effects are concentration-dependent and possibly unattainable at therapeutic-relevant concentrations. These results suggest that the aggregation inhibition activity of RSV and GA in vitro should involve, instead, either the non-covalent binding to oligomeric intermediates or the stabilization of the monomer and/or oligomers through the formation of covalent bonds of the respective quinones with α-syn. In addition, the enhanced aggregation tendency of the peptides observed here could be associated with the formation of non-toxic oligomers, reported for some polyphenols.

Thermodynamics of association of water soluble fullerene derivatives [ $$\hbox {C}_{60}\hbox {(OH)}_{\mathrm{n}}$$ C 60 (OH) n , n = 0, 2, 4, 8 and 12] in aqueous media

The thermodynamics of association of fullerene [ $$\hbox {C}_{60}$$ ] and water-soluble fullerene derivatives, i.e., fullerols [ $$\hbox {C}_{60}\hbox {(OH)}_{\mathrm{n}}$$ , where, n = 2, 4, 8, 12] in aqueous solutions have been studied using molecular dynamics simulations. The potentials of mean force (PMFs) bring out the tendency of aggregation of these nanostructures in water. The extent of hydroxylation seems to have a minor effect on the depth of the contact minima (the first minimum in the PMFs). The positions of the subsequent minima and maxima in the PMFs change with the size of the solute molecules. Higher stability of the contact state of highly hydroxylated fullerols is due to the van der Waals interactions whereas intermolecular solute-solvent hydrogen bonding nearly flattens the PMFs beyond the $$2{\mathrm{nd}}$$ minima for higher fullerols. The solvent contributions to the PMFs for all the solute particles studied here are positive. Entropic and enthalpic contributions to the association of solute molecules are calculated in the isothermal-isobaric (NPT) ensemble. We find that the contact pair formation is governed by entropy with the enthalpic contributions being highly unfavorable, whereas the solvent assisted and solvent separated configurations show entropy-enthalpy compensation. Synopsis: Aqueous solutions of fullerene have found applications in molecular sensing devices, biochemistry and environmental science. Therefore, it is necessary to have a microscopic understanding of the solvation structure of such macromolecules. Association and dynamics of fullerene and fullerols [ $$\hbox {C}_{60}\hbox {(OH)}_{\mathrm{n}}$$ ] in water are addressed by molecular dynamics simulations.

Hydrophobic and Hydrophilic Associations of a Methanol Pair in Aqueous Solution

The association dynamics of a methanol pair in aqueous solution were theoretically studied with QM/EFP-MD and quantum mechanical methods. Stable contact pairs and solvent separated configurations (SS) were found from simulations with a free energy barrier of 2 kcal/mol, revealing the strong tendency of methanol association. The stable contact pairs were further identified as the hydrophobic (CP(A)) and hydrophilic (CP(B)) species, with the CP(A) having a larger population. Although the free energy difference between the CP(A) and CP(B) is negligible with virtually no associated free energy barrier, the slow isomerization dynamics of intermolecular rotations ensures their individual identity. Further mechanistic analysis revealed that only the CP(A) has a direct path to the SS, showing that hydrophobic attraction initiates the association process. A subsequent intermolecular hydrophilic attraction isomerizes CP(A) and CP(B). Therefore, our results show that both the hydrophobic and hydrophilic attractions between methanol molecules play important roles in the association dynamics. The former operates on the longer intermolecular distance, while the latter is effective in contact pairs.

Hydrophobicity within the three-dimensional Mercedes-Benz model: Potential of mean force

We use the three-dimensional Mercedes-Benz model for water and Monte Carlo simulations to study the structure and thermodynamics of the hydrophobic interaction. Radial distribution functions are used to classify different cases of the interaction, namely, contact configurations, solvent separated configurations, and desolvation configurations. The temperature dependence of these cases is shown to be in qualitative agreement with atomistic models of water. In particular, while the energy for the formation of contact configurations is favored by entropy, its strengthening with increasing temperature is accounted for by enthalpy. This is consistent with our simulated heat capacity. An important feature of the model is that it can be used to account for well-converged thermodynamics quantities, e.g., the heat capacity of transfer. Microscopic mechanisms for the temperature dependence of the hydrophobic interaction are discussed at the molecular level based on the conceptual simplicity of the model.

Charge Separation Distance for Flexible Donor−Bridge−Acceptor Systems after Electron-Transfer Quenching

Photoinduced transient dipole experiments are used to measure the effective charge separation distance, which is equivalent to the photoinduced change in dipole moment divided by the electron charge of flexible electron-donor/acceptor systems, D-(CH2)n-A, where D is 4- N,N-dimethylaniline, A is 9-anthryl, and n = 3, 4. We find that the dipole moments increase strongly with solvent polarity. For the compound with n = 4 (DBA4), analysis of dipole signals indicates that the effective charge separation distances in toluene, 1,4-dioxane, ethyl acetate, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, 2-methylpentanone-3, 3-pentanone, and benzonitrile are 2.2, 2.5, 4.5, 4.7, 5.5, 5.5, 4.8, and 6.3 A, respectively. These values can be understood as the root-mean-square charge separation distance in the solutions of different solvents. We assume that the folded contact configuration has a separation distance of 3.5 A, the extended, solvent-separated configuration has a separation distance of 8.0 A, and that they are the only two stable species after electron-transfer quenching. The formation efficiencies of contact radical ion pairs (CRIPs) and solvent-separated radical ion pairs (SSRIPs) are estimated in different solvents. The results indicate that a significant fraction of the ion pairs exist as solvent-separated ion pairs when the dielectric constant of the solvent is larger than 10. These results indicate that electron-transfer quenching can indeed happen at large separations in polar solvents. They also reveal that there is a barrier for ion pairs formed at large separations, hindering collapse to a contact separation of around 3.5 A.

Microscopic Mechanism for Cold Denaturation

We elucidate the mechanism of cold denaturation through constant-pressure simulations for a model of hydrophobic molecules in an explicit solvent. We find that the temperature dependence of the hydrophobic effect induces, facilitates, and is the driving force for cold denaturation. The physical mechanism underlying this phenomenon is identified as the destabilization of hydrophobic contact in favor of solvent-separated configurations, the same mechanism seen in pressure-induced denaturation. A phenomenological explanation proposed for the mechanism is suggested as being responsible for cold denaturation in real proteins.

Enhancing the Hydrophobic Effect in Confined Water Nanodrops

The distribution of hydrophobic solutes, such as methane, enclosed in a nanosized water droplet contained in a reverse micelle of diameter 2.82 nm is investigated using Monte Carlo simulations. The effect of the hydrophobic solute's atomic diameter on the solute-solute potential of mean force is also studied. The study reveals that confinement has a strong influence on the solute's tendency to associate. The potential of mean force exhibits only a single minimum, indicating that the contact pair is the only stable configuration between solutes. The solvent-separated pair that is universally observed for small solutes in bulk water is conspicuously absent. This enhanced hydrophobic effect is attributed to the lack of sufficient water to completely hydrate and stabilize the solvent-separated configurations. The study is expected to be important in understanding the role of hydrophobic forces during protein folding and nucleation under confinement.

Hydrophobic interaction and hydrogen-bond network for a methane pair in liquid water

We employ fully quantum-mechanical molecular dynamics simulations to evaluate the force between two methanes dissolved in water, as a model for hydrophobic association. A stable configuration is found near the methane-methane contact separation, while a shallow second potential minimum occurs for the solvent-separated configuration. The strength and shape of the potential of mean force are in conflict with earlier classical force-field simulations but agree well with a simple hydrophobic burial model which is based on solubility experiments. Examination of solvent dynamics reveals stable water cages at several specific methane-methane separations.

Water-Mediated Three-Particle Interactions between Hydrophobic Solutes: Size, Pressure, and Salt Effects

We use molecular dynamics (MD) simulations of solutions of hydrophobic solutes in explicit water to study the many-body character of hydrophobic interactions at the level of solute−solute−solute three-particle correlations. Comparisons of the calculated three-particle potentials of mean force (PMF) with that obtained by adding solute−solute pair PMFs are used to quantify the many-body effect. Our results shed light on both the range and magnitude of many-body (i.e., nonadditivity) effects. We find that the nonadditivity effects depend on the specific configuration of the three interacting particles and are short-ranged, restricted primarily to locations of the third solute within the first two solvation shells of the primary solute pair. The contact and solvent-separated configurations show anticooperative behavior (i.e., the actual three-particle PMF is less favorable than the pairwise additive approximation), whereas cooperativity is observed at the desolvation barrier. Increasing the solute size makes the nonadditive effects uniformly more anticooperative. Nonadditivity behavior is also short-ranged at higher pressures and in NaCl solutions. Interestingly, increasing pressure changes the nonadditivity effects toward cooperativity, whereas the opposite is true upon the addition of salt to the solution. The implications of these results on more complex self-assembly processes are discussed.

Enthalpy and entropy contributions to the pressure dependence of hydrophobic interactions

We use long molecular dynamics simulations of methane molecules in explicit water at three different temperatures at pressures of 1 and 4000 atm to calculate entropic and enthalpic contributions to the free energy of methane–methane association. In agreement with previous simulation studies, we find that the contact minimum is dominated by entropy whereas the solvent-separated minimum is stabilized by favorable enthalpy of association. Both the entropy and enthalpy at the contact minimum change negligibly with increasing pressure leading to the relative pressure insensitivity of the contact minimum configurations. In contrast, we find that the solvent-separated configurations are increasingly stabilized at higher pressures by enthalpic contributions that prevail over the slightly unfavorable entropic contributions to the free energy. The desolvation barrier is dominated by unfavorable enthalpy of maintaining a dry volume between methanes. However, the increasing height of the desolvation barrier with increasing pressures results from entropy changes at the barrier configurations. Further resolution of the enthalpy of association shows that major contributions to the enthalpy arise from changes in water–water interactions and the mechanical work (PΔV) expended in bringing the methanes to a separation of r. A connection of these thermodynamic features with the underlying changes in water structure is made by calculating methane–methane–water oxygen triplet correlation functions.

Molecular dynamics simulations of pressure effects on hydrophobic interactions.

We report results on the pressure effects on hydrophobic interactions obtained from molecular dynamics simulations of aqueous solutions of methanes in water. A wide range of pressures that is relevant to pressure denaturation of proteins is investigated. The characteristic features of water-mediated interactions between hydrophobic solutes are found to be pressure-dependent. In particular, with increasing pressure we find that (1) the solvent-separated configurations in the solute-solute potential of mean force (PMF) are stabilized with respect to the contact configurations; (2) the desolvation barrier increases monotonically with respect to both contact and solvent-separated configurations; (3) the locations of the minima and the barrier move toward shorter separations; and (4) pressure effects are considerably amplified for larger hydrophobic solutes. Together, these observations lend strong support to the picture of the pressure denaturation process proposed previously by Hummer et al. (Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 1552): with increasing pressure, the transfer of water into protein interior becomes key to the pressure denaturation process, leading to the dissociation of close hydrophobic contacts and subsequent swelling of the hydrophobic protein interior through insertions of water molecules. The pressure dependence of the PMF between larger hydrophobic solutes shows that pressure effects on the interaction between hydrophobic amino acids may be considerably amplified compared to those on the methane-methane PMF.

The aggregation of methane in aqueous solution

Molecular dynamics simulations, 1.0 ns long, of methane particles in water show the existence of a tendency for aggregation of these solutes which increases with temperature in the range 319–351 K. This is measured by a rise in the contact-configuration peak in the methane–methane radial distribution function at the expense of a decrease in the solvent-separated configuration peak. The observed solute–solute interaction reaches a maximum at 351 K before decreasing in magnitude at 358 K. These observations are consistent with an entropy-driven hydrophobic attraction.

Free energy, entropy, and internal energy of hydrophobic interactions: Computer simulations

Hydrophobic interactions are investigated by molecular dynamics computer simulations of the free energy, entropy, and internal energy of association of two methane molecules in water. Recently we reported a computer simulation calculation of the entropy of association of methane in water [J. Am. Chem. Soc. 114, 5875 (1992)], where entropy drives nonpolar solutes together at short distances. Here this method is compared with two other general methods for the calculation of the entropic contribution to the free energy. The calculated thermodynamic quantities for methane association are in good agreement with available experimental measurements. Solute contact configurations are found to be of greater importance than solvent-separated configurations, in conflict with earlier theoretical and simulation studies of similar systems. In some cases, this conflict may be understood in terms of differences in the assumed, model intermolecular potential energies.

Stability of a model beta-sheet in water.

We have used molecular dynamics simulations to determine the stability in water of a model beta-sheet formed by two alanine dipeptide molecules with two intermolecular hydrogen bonds in the closely spaced antiparallel arrangement. In this paper we describe our computations of the binding free energy of the model sheet and a portion of the free energy surface as a function of a reaction co-ordinate for sheet formation. We used the free energy surface to identify stable conformations along the reaction co-ordinate. To determine whether or not the model sheet with two hydrogen bonds is more stable than a single amide hydrogen bond in water, we compared the results of the present calculations to results from our earlier study of linear hydrogen bond formation between two formamide molecules (the formamide "dimer"). The free energy surfaces for the sheet and formamide dimer each have two minima corresponding to locally stable hydrogen-bonded and solvent-separated configurations. The binding free energies of the model sheet and the formamide dimer are -5.5 and -0.34 kcal/mol, respectively. Thus, the model sheet with two hydrogen bonds is quite stable while the simple amide hydrogen bond is only marginally stable. To understand the relative stabilities of the model sheet and formamide dimer in terms of solute-solute and solute-water interactions, we decomposed the free energy differences between hydrogen-bonded and solvent-separated conformations into energetic and entropic contributions. The changes in the peptide-peptide energy and the entropy are roughly twice as large for the sheet as they are for the formamide dimer. The magnitude of the peptide-water energy difference for the sheet is less than twice (by about 3.5 kcal/mol) that for the formamide dimer, and this accounts for the stability of the sheet. The presence of the side-chains and/or blocking groups apparently prevents the amide groups in the sheet from being solvated as favorably in the separated arrangement as in the formamide dimer, where the amide groups are completely exposed to the solvent.

Molecular dynamics and NMR study of methane-water systems

Molecular dynamics of methane-water systems have been studied through computer simulations (MD), nuclear spin relaxation and self diffusion methods (NMR). MD simulation results give support to the concept of hydrophobic hydration by enhancing the water structure around the methane to create a clathrate. Spontaneous contacts between methanes is observed only at high densities, while so-called solvent-separated configurations are present in all simulations. The dynamics of the solvent water molecules is slowed down. In particular, the reorientational motion is sensitive to the presence of methane in solution. The simulated translational diffusion of methanes as solutes is also slowed down, but is higher than observed experimentally. The rotational motion of methanes is very sensitive to variation of the density while, the translational motion of methane is more constant and follows that of water. Methane acts nearly as a free rotor. The simulated reorientational correlation times for methane in water soluti...

Differences between pair and bulk hydrophobic interactions.

It is now well known that the pair interaction between two hydrocarbon molecules in water has distinctly different properties from the bulk hydrophobic interaction familiar to the biochemist, which is modeled by the transfer of a hydrocarbon from aqueous solutions to pure liquid hydrocarbon. We consider experimental data for pair interactions, which have been fitted by a simple empirical potential function, and point out some of their properties. (i) Surface free energy and cosphere overlap models, of the type considered until now, cannot reproduce correctly both the pair and bulk hydrophobic interactions. (ii) Pair interactions though still attractive are strikingly weaker in aqueous solution than in the gas phase, in contrast to the usual view of hydrophobic interactions. (iii) For pair interactions in water, the solvent-separated configuration is less important than the contact configuration if the hydrocarbon has more than two carbon atoms.

Hydrophobic interaction between a methane molecule and a paraffin wall in liquid water

Monte Carlo simulations of the hydrophobic interaction between a spherical CH 4 molecule and a flat paraffin wall yield the surprising result that the water does not drive the methane molecule into contact with the wall, but rather fayours a solvent-separated configuration in which the methane molecule is separated from the wall by one monolayer of water molecules.

Molecular librations and solvent orientational correlations in hydrophobic phenomena

A detailed analysis of the energetic characteristics associated with the solvent in a simulation of a solution containing a pair of apolar spheres immersed in ST2 water solvent is presented. The spheres are separated by a distance corresponding to the so-called solvent-separated hydrophobic interaction. The analysis of local structure is facilitated by the consideration of only near-neighbour solvent–solvent interactions and the use of a coarse-grained time-averaging procedure which removes the high-frequency librational excitation from the underlying hydrogen-bond network. The structure produced is analogous to that termed “V-structure” by Eisenberg and Kauzmann.The results manifest the expected enhancement in intermolecular interactions within the solvation shell, characteristic of higher orientational correlation, and this enhancement is markedly greater in the region which includes solvent that is shared by solute solvation shells. The V-structure obtained is consistent with an underlying network with further enhancement of intermolecular orientational correlations, upon which is superimposed thermal librational excitation. The intermolecular bonding is consistent with local energetic stabilization of the solvent-separated configuration, reinforcing the clathrate-like picture of solvation.