Implicit solvent simulations of DNA and DNA-protein complexes: agreement with explicit solvent vs experiment

Molecular dynamics simulations of biomolecules with implicit solvent reduce the computational cost and complexity of such simulations so that longer time scales and larger system sizes can be reached. While implicit solvent simulations of proteins have become well established, the success of implicit solvent in the simulation of nucleic acids has not been fully established to date. Results obtained in this study demonstrate that stable and efficient simulations of DNA and a protein-DNA complex can be achieved with an implicit solvent model based on continuum dielectric electrostatics. Differences in conformational sampling of DNA with two sets of atomic radii that are used to define the dielectric interface between the solute and the continuum dielectric model of the solvent are investigated. Results suggest that depending on the choice of atomic radii agreement is either closer to experimental data or to explicit solvent simulations. Furthermore, partial conformational transitions toward A-DNA conformations when salt is added within the implicit solvent framework are observed.     

Stability of ion triplets in ionic liquid/lithium salt solutions: Insights from implicit and explicit solvent models and molecular dynamics simulations

Binding energies of ion triplets formed in ionic liquids by Li⁺ with two anions have been studied using quantum‐chemical calculations with implicit and explicit solvent supplemented by molecular dynamics (MD) simulations. Explicit solvent approach confirms variation of solute‐ionic liquid interactions at distances up to 2 nm, resulting from structure of solvation shells induced by electric field of the solute. Binding energies computed in explicit solvent and from the polarizable continuum model approach differ largely, even in sign, but relative values generally agree between these two models. Stabilities of ion triplets obtained in quantum‐chemical calculations for some systems disagree with MD results; the discrepancy is attributed to the difference between static optimized geometries used in quantum chemical modeling and dynamic structures of triplets in MD simulations. © 2015 Wiley Periodicals, Inc.     

Solvation in supercritical water

Solvation in supercritical water under equilibrium and nonequilibrium conditions is studied via molecular dynamics simulations. The influence of solute charge distributions and solvent density on the solvation structures and dynamics is examined with a diatomic probe solute molecule. It is found that the solvation structure varies dramatically with the solute dipole moment, especially in low-density water, in accord with many previous studies on ion solvation. This electrostrictive effect has important consequences for solvation dynamics. In the case of a nonequilibrium solvent relaxation, if there are sufficiently many water molecules close to the solute at the outset of the relaxation, the solvent response measured as a dynamic Stokes shift is almost completely governed by inertial rotations of these water molecules. By contrast, in the opposite case of a low local solvent density near the solute, not only rotations but also translations of water molecules play an important role in solvent relaxation dynamics. The applicability of a linear response is found to be significantly restricted at low water densities.     

Evaluation of DNA Force Fields in Implicit Solvation

DNA structural deformations and dynamics are crucial to its interactions in the cell. Theoretical simulations are essential tools to explore the structure, dynamics, and thermodynamics of biomolecules in a systematic way. Molecular mechanics force fields for DNA have benefited from constant improvements during the last decades. Several studies have evaluated and compared available force fields when the solvent is modeled by explicit molecules. On the other hand, few systematic studies have assessed the quality of duplex DNA models when implicit solvation is employed. The interest of an implicit modeling of the solvent consists in the important gain in the simulation performance and conformational sampling speed. In this study, respective influences of the force field and the implicit solvation model choice on DNA simulation quality are evaluated. To this end, extensive implicit solvent duplex DNA simulations are performed, attempting to reach both conformational and sequence diversity convergence. Structural parameters are extracted from simulations and statistically compared to available experimental and explicit solvation simulation data. Our results quantitatively expose the respective strengths and weaknesses of the different DNA force fields and implicit solvation models studied. This work can lead to the suggestion of improvements to current DNA theoretical models.     

On the different roles of anions and cations in the solvation of enzymes in ionic liquids

The solvation of the enzyme Candida antarctica lipase B (CAL-B) was studied in eight different ionic liquids (ILs). The influence of enzyme-ion interactions on the solvation of CAL-B and the structure of the enzyme-IL interface are analyzed. CAL-B and ILs are described with molecular dynamics (MD) simulations in combination with an atomistic empirical force field. The considered cations are based on imidazolium or guanidinium that are paired with nitrate, tetrafluoroborate or hexafluorophosphate anions. The interactions of CAL-B with ILs are dominated by Coulomb interactions with anions, while the second largest contribution stems from van der Waals interactions with cations. The enzyme-ion interaction strength is determined by the ion size and the magnitude of the ion surface charge. The solvation of CAL-B in ILs is unfavorable compared to water because of large formation energies for the CAL-B solute cages in ILs. The internal energy in the IL and of CAL-B increases linearly with the enzyme-ion interaction strength. The average electrostatic potential on the surface of CAL-B is larger in ILs than in water, due to a weaker screening of charged enzyme residues. Ion densities increased moderately in the vicinity of charged residues and decreased close to non-polar residues. An aggregation of long alkyl chains close to non-polar regions and the active site entrance of CAL-B are observed in one IL that involved long non-polar decyl groups. In ILs that contain 1-butyl-3-methylimidazolium cations, the diffusion of one or two cations into the active site of CAL-B occurs during MD simulations. This suggests a possible obstruction of the active site in these ILs. Overall, the results indicate that small ions lead to a stronger electrostatic screening within the solvent and stronger interactions with the enzyme. Also a large ion surface charge, when more hydrophilic ions are used, increases enzyme-IL interactions. An increase of these interactions destabilizes the enzyme and impedes enzyme solvation due to an increase in solute cage formation energies.     

Implementation and testing of stable, fast implicit solvation in molecular dynamics using the smooth-permittivity finite difference Poisson-Boltzmann method

A fast stable finite difference Poisson-Boltzmann (FDPB) model for implicit solvation in molecular dynamics simulations was developed using the smooth permittivity FDPB method implemented in the OpenEye ZAP libraries. This was interfaced with two widely used molecular dynamics packages, AMBER and CHARMM. Using the CHARMM-ZAP software combination, the implicit solvent model was tested on eight proteins differing in size, structure, and cofactors: calmodulin, horseradish peroxidase (with and without substrate analogue bound), lipid carrier protein, flavodoxin, ubiquitin, cytochrome c, and a de novo designed 3-helix bundle. The stability and accuracy of the implicit solvent simulations was assessed by examining root-mean-squared deviations from crystal structure. This measure was compared with that of a standard explicit water solvent model. In addition we compared experimental and calculated NMR order parameters to obtain a residue level assessment of the accuracy of MD-ZAP for simulating dynamic quantities. Overall, the agreement of the implicit solvent model with experiment was as good as that of explicit water simulations. The implicit solvent method was up to eight times faster than the explicit water simulations, and approximately four times slower than a vacuum simulation (i.e., with no solvent treatment).     

A novel algorithm for creating coarse-grained, density dependent implicit solvent models

Implicit solvent simulations are those in which solvent molecules are not explicitly simulated, and the solute-solute interaction potential is modified to compensate for the implicit solvent effect. Implicit solvation is well known in Brownian dynamics of dilute solutions but offers promise to speed up many other types of molecular simulations as well, including studies of proteins and colloids where the local density can vary considerably. This work examines implicit solvent potentials within a more general coarse-graining framework. While a pairwise potential between solute sites is relatively simple and ubiquitous, an additional parametrization based on the local solute concentration has the possibility to increase the accuracy of the simulations with only a marginal increase in computational cost. We describe here a method in which the radial distribution function and excess chemical potential of solute insertion for a system of Lennard-Jones particles are first measured in a fully explicit, all-particle simulation, and then reproduced across a range of solute particle densities in an implicit solvent simulation.     

A hybrid explicit/implicit solvation method for first-principle molecular dynamics simulations

In this work, we present a hybrid explicit/implicit solvation model, well suited for first-principles molecular dynamics simulations of solute-solvent systems. An effective procedure is presented that allows to reliably model a solute with a few explicit solvation shells, ensuring solvent bulk behavior at the boundary with the continuum. Such an approach is integrated with high-level ab initio methods using localized basis functions to perform first-principles or mixed quantum mechanics/molecular mechanics simulations within the extended-Lagrangian formalism. A careful validation of the model along with illustrative applications to solutions of acetone and glycine radical are presented, considering two solvents of different polarity, namely, water and chloroform. Results show that the present model describes dynamical and solvent effects with an accuracy at least comparable to that of conventional approaches based on periodic boundary conditions.     

Electrostatics of B-DNA in NaCl and CaCl2 solutions: ion size, interionic correlation, and solvent dielectric saturation effects

The epsilon-modified Poisson-Boltzmann (-MPB) equations ( J. Phys. Chem. B, 2007, 111, 5264) have been solved on a three-dimensional grid for an all-atom geometry model of B-DNA. The approach is based on the implicit solvent model including finite sizes of hydrated ions and a dielectric approximation of the ion hydration shell. Results were obtained for the detailed geometry model of B-DNA in dilute and moderately concentrated solutions of NaCl and CaCl(2). All -MPB parameters of ions and dielectric medium were extracted from published results of all-atom molecular dynamics simulations. The study allows evaluations of the ion size, interionic correlation, and the solvent dielectric saturation effects on the ion distributions around DNA. It unambiguously suggests that the difference between the -MPB and Poisson-Boltzmann distributions of ions is low for Na(+) counterions. Such a difference in the case of divalent counterions Ca(2+) is dramatic: the dielectric saturation of the ion hydration shell leads to point-like adsorption of Ca(2+) on the phosphate groups of DNA. The -MPB equations were also applied to calculate the energy of interaction between two B-DNA molecules. Results agree with previously published simulations and experimental data. Some aspects of ion specificity of polyelectrolyte properties are discussed.     

Implicit solvent models for micellization of ionic surfactants

We propose a method for parametrization of implicit solvent models for the simulation of the self-assembly of ionic surfactants into micelles. The parametrization is carried out in two steps. The first step involves atomistic molecular dynamics simulations of headgroups and counterions with explicit solvent to determine structural properties. An implicit solvent model of the headgroup/counterion system is obtained by matching structural quantities between explicit solvent and implicit solvent systems. In the second step, we identify the solvophobic attractions between the tail beads. We determine the solvophobic parameters using grand canonical Monte Carlo simulations with histogram reweighting techniques. The matching objective for the identification of solvophobic attractions is the critical micelle concentration (cmc). We choose sodium dodecyl sulfate as the reference system. On the basis of hydrophobic parameters obtained from this particular model, we study specific ion effects (lithium and potassium instead of sodium) as well as the effect of cationic headgroups (dodecyltrimethylammonium bromide/chloride). Furthermore, the chain length dependence of micellization properties is investigated for sodium alkyl sulfate, with alkyl lengths between 6 and 14. All cases considered give results in broad agreement with experimental data, confirming the transferability of parameters and the generality of the approach.     

Vibrational energy relaxation of a diatomic molecule in a room-temperature ionic liquid

Vibrational energy relaxation (VER) dynamics of a diatomic solute in ionic liquid 1-ethyl-3-methylimidazolium hexafluorophosphate (EMI(+)PF(6) (-)) are studied via equilibrium and nonequilibrium molecular dynamics simulations. The time scale for VER is found to decrease markedly with the increasing solute dipole moment, consonant with many previous studies in polar solvents. A detailed analysis of nonequilibrium results shows that for a dipolar solute, dissipation of an excess solute vibrational energy occurs almost exclusively via the Lennard-Jones interactions between the solute and solvent, while an oscillatory energy exchange between the two is mainly controlled by their electrostatic interactions. Regardless of the anharmonicity of the solute vibrational potential, VER becomes accelerated as the initial vibrational energy increases. This is attributed primarily to the enhancement in variations of the solvent force on the solute bond, induced by large-amplitude solute vibrations. One interesting finding is that if a time variable scaled with the initial excitation energy is employed, dissipation dynamics of the excess vibrational energy of the dipolar solute tend to show a universal behavior irrespective of its initial vibrational state. Comparison with water and acetonitrile shows that overall characteristics of VER in EMI(+)PF(6) (-) are similar to those in acetonitrile, while relaxation in water is much faster than the two. It is also found that the Landau-Teller theory predictions for VER time scale obtained via equilibrium simulations of the solvent force autocorrelation function are in reasonable agreement with the nonequilibrium results.     

Molecular dynamics of minimal B‐DNA

Stable and accurate molecular dynamics (MD) of B‐DNA duplexes can be obtained in inexpensive computational conditions where only the minor groove is filled with water while the bulk solvent is represented implicitly. This model system presents significant theoretical as well as practical interest because, due to its simplicity and exceptional computational performance, it can be employed in simulations of very long DNA fragments. To better understand its properties and clarify the physical background of the effects produced by the limited water shell, dynamics of several different DNA oligomers was studied. It is found that optimal simulation conditions are reached when the explicit water is confined within the minor groove while the major groove is cleaned periodically. The internal solvent mobility appears high enough to observe in the nanosecond time scale spontaneous formation of sequence‐specific hydration patterns known from experiments. It is shown that the model produces stable MD trajectories close to the B‐DNA form regardless of the base pair sequence and that, on the other hand, the dynamics are strongly sequence dependent. Independent observations suggest that B‐DNA with only minor groove hydrated resembles its natural thermodynamic state at low water concentration; therefore, this model system can be tentatively called “minimal B‐DNA.” © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 457–467, 2001     

An efficient hybrid explicit/implicit solvent method for biomolecular simulations

We present a new hybrid explicit/implicit solvent method for dynamics simulations of macromolecular systems. The method models explicitly the hydration of the solute by either a layer or sphere of water molecules, and the generalized Born (GB) theory is used to treat the bulk continuum solvent outside the explicit simulation volume. To reduce the computational cost, we implemented a multigrid method for evaluating the pairwise electrostatic and GB terms. It is shown that for typical ion and protein simulations our method achieves similar equilibrium and dynamical observables as the conventional particle mesh Ewald (PME) method. Simulation timings are reported, which indicate that the hybrid method is much faster than PME, primarily due to a significant reduction in the number of explicit water molecules required to model hydration effects.     

Solvent-averaged potentials for alkali-, earth alkali-, and alkylammonium halide aqueous solutions

We derive effective, solvent-free ion-ion potentials for alkali-, earth alkali-, and alkylammonium halide aqueous solutions. The implicit solvent potentials are parametrized to reproduce experimental osmotic coefficients. The modeling approach minimizes the amount of input required from atomistic (force field) models, which usually predict large variations in the effective ion-ion potentials at short distances. For the smaller ion species, the reported potentials are composed of a Coulomb and a Weeks-Chandler-Andersen term. For larger ions, we find that an additional, attractive potential is required at the contact minimum, which is related to solvent degrees of freedom that are usually not accounted for in standard electrostatics models. The reported potentials provide a simple and accurate force field for use in molecular dynamics and Monte Carlo simulations of (poly-)electrolyte systems.     

Ab-initio molecular dynamics and hybrid explicit-implicit solvation model for aqueous and nonaqueous solvents: GFP chromophore in water and methanol solution as case study

Solute–solvent interactions are proxies for understanding how the electronic density of a chromophore interacts with the environment in a more exhaustive way. The subtle balance between polarization, electrostatic, and non-bonded interactions need to be accurately described to obtain good agreement between simulations and experiments. First principles approaches providing accurate configurational sampling through molecular dynamics may be a suitable choice to describe solvent effects on solute chemical–physical properties and spectroscopic features, such as optical absorption of dyes. In this context, accurate energy potentials, obtained by hybrid implicit/explicit solvation methods along with employing nonperiodic boundary conditions, are required to represent bulk solvent around a large solute–solvent cluster. In this work, a novel strategy to simulate methanol solutions is proposed combining ab initio molecular dynamics, a hybrid implicit/explicit flexible solvent model, nonperiodic boundary conditions, and time dependent density functional theory. As case study, the robustness of the proposed protocol has been gauged by investigating the microsolvation and electronic absorption of the anionic green fluorescent protein chromophore in methanol and aqueous solution. Satisfactory results are obtained, reproducing the microsolvation layout of the chromophore and, as a consequence, the experimental trends shown by the optical absorption in different solvents.     

Simulation of conformational transitions by the restricted perturbation-targeted molecular dynamics method

A method for the simulation of conformational transitions is presented. The method, based on targeted molecular dynamics (TMD), limits the conformational change at each molecular dynamics step to a fixed size, that minimizes the root mean square deviation from the target. The method is more efficient than standard TMD and yields lower energy pathways, but, like the TMD method, requires only a single molecular dynamics simulation. Test calculations and comparisons with standard TMD calculations for the alanine dipeptide with the analytic continuum electrostatics implicit solvent model are presented.     

Partition coefficients of methylated DNA bases obtained from free energy calculations with molecular electron density derived atomic charges

Partition coefficients serve in various areas as pharmacology and environmental sciences to predict the hydrophobicity of different substances. Recently, they have also been used to address the accuracy of force fields for various organic compounds and specifically the methylated DNA bases. In this study, atomic charges were derived by different partitioning methods (Hirshfeld and Minimal Basis Iterative Stockholder) directly from the electron density obtained by electronic structure calculations in a vacuum, with an implicit solvation model or with explicit solvation taking the dynamics of the solute and the solvent into account. To test the ability of these charges to describe electrostatic interactions in force fields for condensed phases, the original atomic charges of the AMBER99 force field were replaced with the new atomic charges and combined with different solvent models to obtain the hydration and chloroform solvation free energies by molecular dynamics simulations. Chloroform–water partition coefficients derived from the obtained free energies were compared to experimental and previously reported values obtained with the GAFF or the AMBER‐99 force field. The results show that good agreement with experimental data is obtained when the polarization of the electron density by the solvent has been taken into account, and when the energy needed to polarize the electron density of the solute has been considered in the transfer free energy. These results were further confirmed by hydration free energies of polar and aromatic amino acid side chain analogs. Comparison of the two partitioning methods, Hirshfeld‐I and Minimal Basis Iterative Stockholder (MBIS), revealed some deficiencies in the Hirshfeld‐I method related to the unstable isolated anionic nitrogen pro‐atom used in the method. Hydration free energies and partitioning coefficients obtained with atomic charges from the MBIS partitioning method accounting for polarization by the implicit solvation model are in good agreement with the experimental values. © 2018 Wiley Periodicals, Inc.