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In molecular dynamics simulations, dynamically consistent coarse-grained (CG) models commonly use stochastic thermostats to model friction and fluctuations that are lost in a CG description. While Markovian, i.e., time-local, formulations of such thermostats allow for an accurate representation of diffusivities/long-time dynamics, a correct description of the dynamics on all time scales generally requires non-Markovian, i.e., non-time-local, thermostats. These thermostats typically take the form of a Generalized Langevin Equation (GLE) determined by a memory kernel. In this work, we use a Markovian embedded formulation of a position-independent GLE thermostat acting independently on each CG degree of freedom. Extracting the memory kernel of this CG model from atomistic reference data requires several approximations. Therefore, this task is best understood as an inverse problem. While our recently proposed approximate Newton scheme allows for the iterative optimization of memory kernels (IOMK), Markovian embedding remained potentially error-prone and computationally expensive. In this work, we present an IOMK-Gauss–Newton scheme (IOMK-GN) based on IOMK that allows for the direct parameterization of a Markovian embedded model. [ABSTRACT FROM AUTHOR]

Coarse-grained (CG) models informed from molecular dynamics simulations provide a way to represent the structure of an underlying all-atom (AA) model by deriving an effective interaction potential. However, this leads to a speed-up in dynamics due to the lost friction, which is especially pronounced in CG implicit solvent models. Applying a thermostat based on the Langevin equation (LE) provides a way to represent the long-time dynamics of CG particles by reintroducing friction to the system. To improve the representability of CG models of heterogeneous molecular mixtures and their transferability over the mixture compositions, we parameterize an LE thermostat in which the friction coefficient depends on the local particle density (LD). The thermostat friction was iteratively optimized with a Markovian variant of the recently introduced Iterative Optimization of Memory Kernels (IOMK) method. We simulated tert-butanol/water mixtures over a range of compositions, which show a distinct clustering behavior. Our model with LD-dependent friction reproduces the AA diffusion coefficients well over the full range of mixtures and is, therefore, transferable with respect to dynamics. [ABSTRACT FROM AUTHOR]

The analysis of water density fluctuations in the hydration shell of nonpolar solutes provides insights into water-mediated interactions, especially hydrophobic interactions. These fluctuations are sensitive to small perturbations due to changes in thermodynamic conditions, such as temperature and pressure, but also to the presence of cosolutes, such as salts or small organic molecules. Herein, we investigate the effect of two classes of adsorbing cosolutes, using urea and methanol as representatives, on the fluctuations in energy and solvent density within the solvation shell of a model extended hydrophobic solute. We focus on the interactions of the cosolutes with the hydrophobic hydration shell, rather than with the solute itself, which though important remain largely unexplored. We calculate and analyze the interfacial partial molar energy of the cosolute, using a methodology based on the small system method. This approach provides correlated solvent density and energy fluctuations and allows us to decompose them into contributions due to interactions between the different components present in the solvation shell of the solute. The results show that adsorbed urea molecules interact more favorably with water than nonadsorbed urea molecules, which leads to the attenuation of interfacial density fluctuations and thus to the stabilization of the solvation shell. By contrast, the adsorbed methanol molecules interact preferably with other methanol molecules in the solvation shell, leading to a nano-phase segregated structure, which enhances interfacial fluctuations. [ABSTRACT FROM AUTHOR]

Coarse-grained (CG) simulation models of condensed-phase systems can be derived with well-established methods that perform coarse-graining in space and provide an effective Hamiltonian with which some of the structural and thermodynamic properties of the underlying fine-grained (FG) reference system can be represented. Coarse-graining in time potentially provides CG models that furthermore represent dynamic properties. However, systematic efforts in this direction have so far been limited, especially for moderately coarse-grained, chemistry-specific systems with complicated conservative interactions. With the aim of representing structural, thermodynamic, and dynamic properties in CG simulations of multi-component molecular systems, we investigated a recently introduced method in which the force on a CG particle originates from conservative interactions with surrounding particles and non-Markovian dissipative interactions, the latter introduced by means of a colored-noise thermostat. We examined two different methods to derive isotropic memory kernels required for integrating the corresponding generalized Langevin equation (GLE) of motion, based on the orthogonal dynamics of the FG forces and on an iterative optimization scheme. As a proof of concept, we coarse-grain single-component molecular liquids (cyclohexane, tetrachloromethane) and ideal and non-ideal binary mixtures of cyclohexane/tetrachloromethane and ethanol/tetrachloromethane, respectively. We find that for all systems, the FG single particle velocity auto-correlation functions and, consequently, both the short time and long time diffusion coefficients can be quantitatively reproduced with the CG-GLE models. We furthermore demonstrate that the present GLE-approach leads to an improved description of the rate with which the spatial correlations decay, which is artificially accelerated in the absence of dissipation. [ABSTRACT FROM AUTHOR]

We report a computer simulation study of the effect of trimethylamine N-oxide (TMAO) on the pressure stability of the hydrophobic contact interaction of two nonpolar α-helices. We found that TMAO counterbalanced the disruptive effect of pressure destabilization on account of an earlier reported electronic polarization effect that led to an increased TMAO dipole moment under compression of the solvent. This direct stabilization mechanism became ineffective when the dipole polarization of TMAO was not considered and was linked to nonspecific van der Waals interactions of TMAO with the nonpolar surfaces of the two helices, which became weaker as TMAO became stronger polarized at high pressure. The corresponding thermodynamic driving forces are discussed and should be generic for hydrophobic interactions under high pressure. The proposed mechanism suggests that TMAO stands out as a piezolyte among stabilizing osmolytes, potentially protecting biological assemblies formed by hydrophobic interactions under extreme pressure conditions. [ABSTRACT FROM AUTHOR]

The development of dynamically consistent coarse-grained models for molecular simulations is often based on generalized Langevin equations, motivated by the application of the projection operator formalism (Mori–Zwanzig theory). While Mori's projection operator yields linear generalized Langevin equations that can be computationally efficiently implemented in numerical simulations, the downside is that Mori's generalized Langevin equation does not encompass the multi-body potential of mean force required to correctly encode structural and thermodynamic properties in coarse-grained many-body systems. Zwanzig's projection operator yields nonlinear generalized Langevin equations including the multi-body potential of mean force, while the remaining force contributions are not as cheap to implement in molecular simulation without making it formally hard to justify approximations. For many-particle coarse-grained models, due to computational and conceptual simplicity, an often used approach is to combine nonlinear conservative interactions with linear expressions to model dissipation. In a previous study [V. Klippenstein and N. F. A. van der Vegt, J. Chem. Phys. 154, 191102 (2021)], we proposed a method to parameterize such models to achieve dynamic consistency in coarse-grained models, allowing us to reconcile Mori's and Zwanzig's approach for practical purposes. In the current study, by applying the same strategy, we develop coarse-grained implicit solvent models for the continuous Asakura–Oosawa model, which under certain conditions allows us to develop very accurate coarse-grained potentials. By developing coarse-grained models for different reference systems with varying parameters, we test the broader applicability of the proposed procedure and demonstrate the relevance of accurate coarse-grained potentials in bottom-up derived dissipative models. We study how different system parameters affect the dynamic representability of the coarse-grained models. In particular, we find that the quality of the coarse-grained potential is crucial to correctly model the backscattering effect due to collisions on the coarse-grained scale. As hydrodynamic interactions are not explicitly modeled in the presented coarse-graining approach, deviations are observed in the long-time dynamics. The Asakura–Oosawa model allows for the tuning of system parameters to gain an improved understanding of this limitation. We also propose three new iterative optimization schemes to fine-tune the generalized Langevin thermostat to exactly match the reference velocity-autocorrelation function. [ABSTRACT FROM AUTHOR]

The effect of trimethylamine-N-oxide (TMAO) on hydrophobic solvation and hydrophobic interactions of methane has been studied with Molecular Dynamics simulations in the temperature range between 280 and 370 K at 1 bar ambient pressure. We observe a temperature transition in the effect of TMAO on the aqueous solubility of methane. At low temperature (280 K), methane is preferentially hydrated, causing TMAO to reduce its solubility in water, while above 320 K, methane preferentially interacts with TMAO, causing TMAO to promote its solubility in water. Based on a statistical-mechanical analysis of the excess chemical potential of methane, we find that the reversible work of creating a repulsive methane cavity opposes the solubility of methane in TMAO/water solution more than in pure water. Below 320 K, this solvent-excluded volume effect overcompensates the contribution of methane–TMAO van der Waals interactions, which promote the solvation of methane and are observed at all temperatures. These van der Waals interactions with the methyl groups of TMAO tip the balance above 320 K where the effect of TMAO on solvent-excluded volume is smaller. We furthermore find that the effective attraction between dissolved methane solutes increases with the increasing TMAO concentration. This observation correlates with a reduction in the methane solubility below 320 K but with an increase in methane solubility at higher temperatures. [ABSTRACT FROM AUTHOR]

The ability of various cosolutes and cosolvents to enhance or quench solvent density fluctuations at solute–water interfaces has crucial implications on the conformational equilibrium of macromolecules such as polymers and proteins. Herein, we use an extended hydrophobic solute as a model system to study the effect of urea and methanol on the density fluctuations in the solute's solvation shell and the resulting thermodynamics. On strengthening the solute–water/cosolute repulsive interaction, we observe distinct trends in the mutual affinities between various species in, and the thermodynamic properties of, the solvation shell. These trends strongly follow the respective trends in the preferential adsorption of urea and methanol: solute–water/cosolute repulsion strengthens, urea accumulation decreases, and methanol accumulation increases. Preferential accumulation of urea is found to quench the density fluctuations around the extended solute, leading to a decrease in the compressibility of the solvation shell. In contrast, methanol accumulation enhances the density fluctuations, leading to an increase in the compressibility. The mode of action of urea and methanol seems to be strongly coupled to their hydration behavior. The observations from this simple model is discussed in relation to urea driven swelling and methanol induced collapse of some well-known thermo-responsive polymers. [ABSTRACT FROM AUTHOR]

We propose a route for parameterizing isotropic (generalized) Langevin [(G)LE] thermostats with the aim to correct the dynamics of coarse-grained (CG) models with pairwise conservative interactions. The approach is based on the Mori–Zwanzig formalism and derives the memory kernels from Q-projected time correlation functions. Bottom-up informed (GLE and LE) thermostats for a CG star-polymer melt are investigated, and it is demonstrated that the inclusion of memory in the CG simulation leads to predictions of polymer diffusion in quantitative agreement with fine-grained simulations. Interestingly, memory effects are observed in the diffusive regime. We demonstrate that previously neglected cross-correlations between the "irrelevant" and the CG degree of freedom are important and lie at the origin of shortcomings in previous CG simulations. [ABSTRACT FROM AUTHOR]

Cosolvent effects on the coil–globule transitions in aqueous polymer solutions are not well understood, especially in the case of amphiphilic cosolvents that preferentially adsorb on the polymer and lead to both polymer swelling and collapse. Although a predominant focus in the literature has been placed on the role of polymer–cosolvent attractive interactions, our recent work has shown that excluded-volume interactions (repulsive interactions) can drive both preferential adsorption of the cosolvent and polymer collapse via a surfactant-like mechanism. Here, we further study the role of polymer–(co)solvent attractive interactions in two kinds of polymer solutions, namely, good solvent (water)–good cosolvent (alcohol) (GSGC) and poor solvent–good cosolvent (PSGC) solutions, both of which exhibit preferential adsorption of the cosolvent and a non-monotonic change in the polymer radius of gyration with the addition of the cosolvent. Interestingly, at low concentrations, the polymer–(co)solvent energetic interactions oppose polymer collapse in the GSGC solutions and contrarily support polymer collapse in the PSGC solutions, indicating the importance of the underlying polymer chemistry. Even though the alcohol molecules are preferentially adsorbed on the polymer, the trends of the energetic interactions at low cosolvent concentrations are dominated by the polymer–water energetic interactions in both the cases. Therefore, polymer–(co)solvent energetic interactions can either reinforce or compensate the surfactant-like mechanism, and it is this interplay that drives coil-to-globule transitions in polymer solutions. These results have implications for rationalizing the cononsolvency transitions in real systems such as polyacrylamides in aqueous alcohol solutions where the understanding of microscopic driving forces is still debatable. [ABSTRACT FROM AUTHOR]

In this paper, new Newton and Gauss–Newton methods for iterative coarse-graining based on integral equation theory are evaluated and extended. In these methods, the potential update is calculated from the current and target radial distribution function, similar to iterative Boltzmann inversion, but gives a potential update of quality comparable with inverse Monte Carlo. This works well for the coarse-graining of molecules to single beads, which we demonstrate for water. We also extend the methods to systems that include coarse-grained bonded interactions and examine their convergence behavior. Finally, using the Gauss–Newton method with constraints, we derive a model for single bead methanol in implicit water, which matches the osmotic pressure of the atomistic reference. An implementation of all new methods is provided for the open-source VOTCA package. [ABSTRACT FROM AUTHOR]

Several molecular coarse-graining methods have been proposed in recent years to derive chemical- and state-point transferable force fields. While these force fields describe structural and thermodynamic properties in good agreement with fine-grained models and experiments, dynamic properties are usually overestimated. Herein, we examine if the long-time dynamic properties of molecular coarse-grained (CG) systems can be correctly represented by employing a dissipative particle dynamics (DPD) thermostat, which is "bottom-up informed" by means of a variant of the Markovian Mori-Zwanzig (MZ) DPD coarse-graining method. We report single-site and multiple-site CG models for a monomer, dimer, and 24mer based on 2,2-dimethyl propane as a chemical repeat unit and report data obtained from MZ-DPD simulations of liquids, polymer solutions, and polymer melts. We find that despite incomplete time scale separation of the molecular CG model, MZ-DPD achieves quantitative accuracy in predicting diffusive dynamics in single-component liquids and polymer solutions (24mers in a dimer solvent). We also find that MZ-DPD simulations of molecular penetrant diffusion in polymer networks do not reach quantitative agreement with the fine-grained model. Modeling diffusion governed by the activated barrier crossing of small molecular penetrants in these dense systems requires an accurate description of energy barriers, presumably combined with the treatment of memory effects. The use of a MZ-DPD thermostat extends the scope and applicability of molecular CG models for multicomponent systems where a correct description of the relative diffusion rates of the different components is important. [ABSTRACT FROM AUTHOR]

Non-polarizable force fields for hydrated ions not always accurately describe short-range ion-ion interactions, frequently leading to artificial ion clustering in bulk aqueous solutions. This can be avoided by adjusting the nonbonded anion-cation or cation-water Lennard-Jones parameters. This approach has been successfully applied to different systems, but the parameterization is demanding owing to the necessity of separate investigations of each ion pair. Alternatively, polarization effects may effectively be accounted for using the electronic continuum correction (ECC) of Leontyev et al. [J. Chem. Phys. 119, 8024 (2003)], which involves scaling the ionic charges with the inverse square-root of the water high-frequency dielectric permittivity. ECC has proven to perform well for monovalent salts as well as for divalent salts in water. Its performance, however, for multivalent salts with higher valency remains unexplored. The present work illustrates the applicability of the ECC model to trivalent K3PO4 and divalent K2HPO4 in water. We demonstrate that the ECC models, without additional tuning of force field parameters, provide an accurate description of water-mediated interactions between salt ions. This results in predictions of the osmotic coefficients of aqueous K3PO4 and K2HPO4 solutions in good agreement with experimental data. Analysis of ion pairing thermodynamics in terms of contact ion pair (CIP), solvent-separated ion pair, and double solvent-separated ion pair contributions shows that potassium-phosphate CIP formation is stronger with trivalent than with divalent phosphate ions. [ABSTRACT FROM AUTHOR]

This work investigates the question if surface capillary waves (CWs) affect interfacial solvation thermodynamic properties that determine the propensity of small molecules toward the liquid-vapor interface.We focus on (1) the evaluation of these properties from molecular simulations in a practical manner and (2) understanding them from the perspective of theories in solvation thermodynamics, especially solvent reorganization effects. Concerning the former objective, we propose a computational method that exploits the relationship between an external field acting on the liquid-vapor interface and the magnitude of CWs. The system considered contains the solvent, an externally applied field ( f ) and the solute molecule fixed at a particular location. The magnitude of f is selected to induce changes in CWs. The difference between the solvation free energies computed in the presence and in the absence of f is then shown to quantify the contribution of CWs to interfacial solvation. We describe the implementation of this method in the canonical ensemble by using a Lennard-Jones solvent and a non-ionic solute. Results are shown for three types of solutes that differ in the nature of short-ranged repulsive (hard-core) interactions. Overall, we observe that CWs have a negligible or very small effect on the interfacial solvation free energy of a solute molecule fixed near the liquid-vapor interface for the above systems. We also explain how the effects of pinning or dampening of CWs caused by a fixed solute are effectively compensated and do not contribute to the solvation free energy. [ABSTRACT FROM AUTHOR]

We address the question of how reducing the number of degrees of freedom modifies the interfacial thermodynamic properties of heterogeneous solid-liquid systems. We consider the example of n-hexane interacting with multi-layer graphene which we model both with fully atomistic and coarse-grained (CG) models. The CG models are obtained by means of the conditional reversible work (CRW) method. The interfacial thermodynamics of these models is characterized by the solid-liquid work of adhesion WSL calculated by means of the dry-surface methodology through molecular dynamics simulations. We find that the CRWpotentials lead to values of WSL that are larger than the atomistic ones. Clear understanding of the relationship between the structure of n-hexane in the vicinity of the surface and WSL is elucidated through a detailed study of the energy and entropy components of WSL. We highlight the crucial role played by the solid-liquid energy fluctuations. Our approach suggests that CG potentials should be designed in such a way that they preserve the range of solid-liquid interaction energies, but also their fluctuations in order to preserve the reference atomistic value of WSL. Our study thus opens perspectives into deriving CG interaction potentials that preserve the thermodynamics of solid-liquid contacts and will find application in studies that intend to address materials driven by interfaces. [ABSTRACT FROM AUTHOR]

The hydration process of side chain analogue molecules differs from that of the actual amino acid side chains in peptides and proteins owing to the effects of the peptide backbone on the aqueous solvent environment. A recent molecular simulation study has provided evidence that all nonpolar side chains, attached to a short peptide backbone, are considerably less hydrophobic than the free side chain analogue molecules. In contrast to this, the hydrophilicity of the polar side chains is hardly affected by the backbone. To analyze the origin of these observations, we here present a molecular simulation study on temperature dependent solvation free energies of nonpolar and polar side chains attached to a short peptide backbone. The estimated solvation entropies and enthalpies of the various amino acid side chains are compared with existing side chain analogue data. The solvation entropies and enthalpies of the polar side chains are negative, but in absolute magnitude smaller compared with the corresponding analogue data. The observed differences are large; however, owing to a nearly perfect enthalpy-entropy compensation, the solvation free energies of polar side chains remain largely unaffected by the peptide backbone. We find that a similar compensation does not apply to the nonpolar side chains; while the backbone greatly reduces the unfavorable solvation entropies, the solvation enthalpies are either more favorable or only marginally affected. This results in a very small unfavorable free energy cost, or even free energy gain, of solvating the nonpolar side chains in strong contrast to solvation of small hydrophobic or nonpolar molecules in bulk water. The solvation free energies of nonpolar side chains have been furthermore decomposed into a repulsive cavity formation contribution and an attractive dispersion free energy contribution. We find that cavity formation next to the peptide backbone is entropically favored over formation of similar sized nonpolar side chain cavities in bulk water, in agreement with earlier work in the literature on analysis of cavity fluctuations at nonpolar molecular surfaces. The cavity and dispersion interaction contributions correlate quite well with the solvent accessible surface area of the nonpolar side chains attached to the backbone. This correlation however is weak for the overall solvation free energies owing to the fact that the cavity and dispersion free energy contributions are almost exactly cancelling each other. [ABSTRACT FROM AUTHOR]

Molecular simulations of soft matter systems have been performed in recent years using a variety of systematically coarse-grained models. With these models, structural or thermodynamic properties can be quite accurately represented while the prediction of dynamic properties remains difficult, especially for multi-component systems. In this work, we use constraint molecular dynamics simulations for calculating dissipative pair forces which are used together with conditional reversible work (CRW) conservative forces in dissipative particle dynamics (DPD) simulations. The combined CRWDPD approach aims to extend the representability of CRW models to dynamic properties and uses a bottom-up approach. Dissipative pair forces are derived from fluctuations of the direct atomistic forces between mapped groups. The conservative CRW potential is obtained from a similar series of constraint dynamics simulations and represents the reversible work performed to couple the direct atomistic interactions between the mapped atom groups. Neopentane, tetrachloromethane, cyclohexane, and n-hexane have been considered as model systems. These molecular liquids are simulated with atomistic molecular dynamics, coarse-grained molecular dynamics, and DPD. We find that the CRW-DPD models reproduce the liquid structure and diffusive dynamics of the liquid systems in reasonable agreement with the atomistic models when using single-site mapping schemes with beads containing five or six heavy atoms. For a two-site representation of n-hexane (3 carbons per bead), time scale separation can no longer be assumed and the DPD approach consequently fails to reproduce the atomistic dynamics. [ABSTRACT FROM AUTHOR]