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.     

Binding energies of five molecular pincers calculated by explicit and implicit solvent models

Molecular pincers or tweezers are designed to hold and release the target molecule. Potential applications involve drug distribution in medicine, environment technologies, or microindustrial techniques. Typically, the binding is dominated by van der Waals forces. Modeling of such complexes can significantly enhance their design; yet obtaining accurate complexation energies by theory is difficult. In this study, density functional theory (DFT) computations combined with dielectric continuum solvent model are compared with the potential of mean force approach using umbrella sampling and the weighted histogram analysis method (WHAM) with molecular dynamics (MD) simulations. For DFT, functional and basis set effects are discussed. The computed results are compared to experimental data based on NMR spectroscopic measurements of five synthesized tweezers based on the Tröger's basis. Whereas the DFT computations correctly provided the observed trends in complex stability, they failed to produce realistic magnitudes of complexation energies. Typically, the binding was overestimated by DFT if compared to experiment. The simpler semiempirical PM6‐DH2X scheme proposed lately yielded better magnitudes of the binding energies than DFT but not the right order. The MD‐WHAM simulations provided the most realistic Gibbs binding energies, although the approximate MD force fields were not able to reproduce completely the ordering of relative stabilities of model complexes found by NMR. Yet the modeling provides interesting insight into the complex geometry and flexibility and appears as a useful tool in the tweezers' design. © 2012 Wiley Periodicals, Inc.     

Free energies of solvation in the context of protein folding: Implications for implicit and explicit solvent models

Implicit solvent models for biomolecular simulations have been developed to use in place of more expensive explicit models; however, these models make many assumptions and approximations that are likely to affect accuracy. Here, the changes in free energies of solvation upon folding of several fast folding proteins are calculated from previously run μs–ms simulations with a number of implicit solvent models and compared to the values needed to be consistent with the explicit solvent model used in the simulations. In the majority of cases, there is a significant and substantial difference between the values calculated from the two approaches that is robust to the details of the calculations. These differences could only be remedied by selecting values for the model parameters—the internal dielectric constant for the polar term and the surface tension coefficient for the nonpolar term—that were system‐specific or physically unrealistic. We discuss the potential implications of our findings for both implicit and explicit solvent simulations. © 2015 Wiley Periodicals, Inc.     

Proton binding to proteins: pK(a) calculations with explicit and implicit solvent models

Ionizable residues play important roles in protein structure and activity, and proton binding is a valuable reporter of electrostatic interactions in these systems. We use molecular dynamics free energy simulations (MDFE) to compute proton pKa shifts, relative to a model compound in solution, for three aspartate side chains in two proteins. Simulations with explicit solvent and with an implicit, dielectric continuum solvent are reported. The implicit solvent simulations use the generalized Born (GB) model, which provides an approximate, analytical solution to Poisson's equation. With explicit solvent, the direction of the pKa shifts is correct in all three cases with one force field (AMBER) and in two out of three cases with another (CHARMM). For two aspartates, the dielectric response to ionization is found to be linear, even though the separate protein and solvent responses can be nonlinear. For thioredoxin Asp26, nonlinearity arises from the presence of two substates that correspond to the two possible orientations of the protonated carboxylate. For this side chain, which is partly buried and has a large pKa upshift, very long simulations are needed to correctly sample several slow degrees of freedom that reorganize in response to the ionization. Thus, nearby Lys57 rotates to form a salt bridge and becomes buried, while three waters intercalate along the opposite edge of Asp26. Such strong and anisotropic reorganization is very difficult to predict with Poisson-Boltzmann methods that only consider electrostatic interactions and employ a single protein structure. In contrast, MDFE with a GB dielectric continuum solvent, used for the first time for pKa calculations, can describe protein reorganization accurately and gives encouraging agreement with experiment and with the explicit solvent simulations.     

Solvent models for protein–ligand binding: Comparison of implicit solvent poisson and surface generalized born models with explicit solvent simulations

Solvent effects play a crucial role in mediating the interactions between proteins and their ligands. Implicit solvent models offer some advantages for modeling these interactions, but they have not been parameterized on such complex problems, and therefore, it is not clear how reliable they are. We have studied the binding of an octapeptide ligand to the murine MHC class I protein using both explicit solvent and implicit solvent models. The solvation free energy calculations are more than 10³ faster using the Surface Generalized Born implicit solvent model compared to FEP simulations with explicit solvent. For some of the electrostatic calculations needed to estimate the binding free energy, there is near quantitative agreement between the explicit and implicit solvent model results; overall, the qualitative trends in the binding predicted by the explicit solvent FEP simulations are reproduced by the implicit solvent model. With an appropriate choice of reference system based on the binding of the discharged ligand, electrostatic interactions are found to enhance the binding affinity because the favorable Coulomb interaction energy between the ligand and protein more than compensates for the unfavorable free energy cost of partially desolvating the ligand upon binding. Some of the effects of protein flexibility and thermal motions on charging the peptide in the solvated complex are also considered. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 591–607, 2001     

Competition between intramolecular hydrogen bonds and solvation in phosphorylated peptides: simulations with explicit and implicit solvent

The atomic-level mechanisms of protein regulation by post-translational phosphorylation remain poorly understood, except in a few well-studied systems. Molecular mechanics simulations can in principle be used to help understand and predict the effects of protein phosphorylation, but the accuracy of the results will of course depend on the quality of the force field parameters for the phosphorylated residues as well as the quality of the solvent model. The phosphorylated residues typically carry a -2 charge at physiological pH; however, the effects of phosphorylation can sometimes be mimicked by substituting Asp or Glu for the phosphorylated residue. Here we examine the suitability of explicit and implicit solvent models for simulating phospho-serine in both the -1 and -2 charge states. Specifically, we simulate a capped phosphorylated peptide, Ace-Gly-Ser-pSer-Ser-Nme, and compare the results to each other and to experimental observables from an NMR experiment. The first major conclusion is that explicit water models (TIP3P, TIP4P and SPC/E) and a Generalized Born implicit solvent model provide reasonable agreement with the experimental observables, given appropriate partial charges for the phosphate group. The Generalized Born results, however, show greater hydrogen bonding propensity than the explicit solvent results. Distance dependent dielectric treatments perform poorly. The second major conclusion is that many ensemble-averaged properties obtained for the phosphopeptide in the -1 and -2 charge states are strikingly similar; the -1 species has a slightly higher propensity to form internal hydrogen bonds. All of the results can be rationalized by quantifying the strength of the P-O/H-N hydrogen bond, which depends on a sensitive balance between strongly favorable charge/dipole and dipole/dipole interactions and strongly unfavorable desolvation.     

Full MP2 study of solvent implicit and explicit effect on tautomers of Dithio-Biuret

Dithio biuret conformers were optimised and frequency calculations were performed at MP2/6–311++G(d,p) level of theory. Classification of conformers was done to five different tautomers and the most stable conformer of each tautomer was selected. Tautomer 3 having trans conformation of amino and thiocarbonyl functional group was the most stable tautomer in the gas phase. Optimisation and frequency calculations were also done in four different solvents as follows: benzene, acetonitrile, DMSO and water. Stability of tautomers were compared in these solvents to explore effect of polarity on stabilisation of tautomers. Inter-conversion of selected tautomers was investigated both in the gas phase and in four different media. Results showed that when solvent is used as an implicit media, it has negligible effect on proton transfer. Water-explicit effect was also investigated and the results exhibited high dependency of proton transfer mechanism on water molecules when they participate in breaking and formation of bonds.     

A new interface for coupling solid phase microextraction with liquid chromatography

A modified Rheodyne 7520 microsample injector was used as a new solid phase microextraction (SPME)–liquid chromatography (LC) interface. The modification was focused on the construction of a new sample rotor, which was built by gluing two sample rotors together. The new sample rotor was further reinforced with 3 pieces of stainless steel tubing. The enlarged central flow passage in the new sample rotor was used as a desorption chamber. SPME fiber desorption occurred in static mode. But all desorption solvent in the desorption chamber was injected into LC system with the interface. The analytical performance of the interface was evaluated by SPME–LC analysis of PAHs in water. At least 90% polycyclic aromatic hydrocarbons (PAHs) were desorbed from a polyacrylonitrile (PAN)/C18 bonded fuse silica fiber in 30 s. And injection was completed in 20 s. About 10–20% total carryovers were found on the fiber and in the interface. The carryover in the interface was eliminated by flushing the desorption chamber with acetonitrile at 1 mL min⁻¹ for 2 min. The repeatability of the method was from 2% to 8%. The limit of detection (LOD) was in the mid pg mL⁻¹ range. The linear ranges were from 0.1 to 100 ng mL⁻¹. The new SPME–LC interface was reliable for coupling SPME with LC for both qualitative and quantitative analysis.     

Secondary structure bias in generalized Born solvent models: comparison of conformational ensembles and free energy of solvent polarization from explicit and implicit solvation

The effects of the use of three generalized Born (GB) implicit solvent models on the thermodynamics of a simple polyalanine peptide are studied via comparing several hundred nanoseconds of well-converged replica exchange molecular dynamics (REMD) simulations using explicit TIP3P solvent to REMD simulations with the GB solvent models. It is found that when compared to REMD simulations using TIP3P the GB REMD simulations contain significant differences in secondary structure populations, most notably an overabundance of alpha-helical secondary structure. This discrepancy is explored via comparison of the differences in the electrostatic component of the free energy of solvation (DeltaDeltaG(pol)) between TIP3P (via thermodynamic Integration calculations), the GB models, and an implicit solvent model based on the Poisson equation (PE). The electrostatic components of the solvation free energies are calculated using each solvent model for four representative conformations of Ala10. Since the PE model is found to have the best performance with respect to reproducing TIP3P DeltaDeltaG(pol) values, effective Born radii from the GB models are compared to effective Born radii calculated with PE (so-called perfect radii), and significant and numerous deviations in GB radii from perfect radii are found in all GB models. The effect of these deviations on the solvation free energy is discussed, and it is shown that even when perfect radii are used the agreement of GB with TIP3P DeltaDeltaG(pol) values does not improve. This suggests a limit to the optimization of the effective Born radius calculation and that future efforts to improve the accuracy of GB models must extend beyond such optimizations.     

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.     

Elucidating the vibrational spectra of hydrogen-bonded aggregates in solution: electronic structure calculations with implicit solvent and first-principles molecular dynamics simulations with explicit solvent for 1-hexanol in n-hexane

Fourier transform infrared spectroscopy is a popular method for the experimental investigation of hydrogen-bonded aggregates, but linking spectral information to microscopic information on aggregate size distribution and aggregate architecture is an arduous task. Static electronic structure calculations with an implicit solvent model, Car-Parrinello molecular dynamics (CPMD) using the Becke-Lee-Yang-Parr (BLYP) exchange and correlation energy functionals and classical molecular dynamics simulations for the all-atom version of the optimized parameters for liquid simulations (OPLS-AA) force field were carried out for an ensemble of 1-hexanol aggregates solvated in n-hexane. The initial configurations for these calculations were size-selected from a distribution of aggregates obtained from a large-scale Monte Carlo simulation. The vibrational spectra computed from the static electronic structure calculations for monomers and dimers and from the CPMD simulations for aggregates up to pentamers demonstrate the extent of the contribution of dangling or nondonating hydroxyl groups found in linear and branched aggregates to the "monomeric" peak. Furthermore, the computed spectra show that there is no simple relationship between peak shift and aggregate size nor architecture, but the effect of hydrogen-bond cooperativity is shown to differentiate polymer-like (cooperative) and dimer-like (noncooperative) hydrogen bonds in the vibrational spectrum. In contrast to the static electronic structure calculations and the CPMD simulations, the classical molecular dynamics simulations greatly underestimate the vibrational peak shift due to hydrogen bonding.     

A new sheathless electrospray interface for coupling of capillary electrophoresis to ion-trap mass spectrometry

A simple laboratory-made sheathless electrospray interface for coupling of capillary electrophoresis to ion-trap mass spectrometry (CE/MS) was developed. The interface was machined in-house and it was designed to be freely interchangeable with the commercially available ionization sources for the mass spectrometer. Sharpened fused-silica capillaries were coated with nickel by a simple electrodeless plating procedure and were used as all-in-one columns/emitters. The electrodeless plating produced a 2-5- micro m thick smooth nickel layer that lasted for more than 8 h of continuous electrospraying. The performance of the CE/MS interface was examined by using four cationic imipramine derivatives as test substances. Relative detection limits were calculated on the basis of the extracted ion electrophorograms and were in the range 6-130 nmol/L, corresponding to absolute detection limits in the range of 20-400 amol. The system was applied for analysis of impurities in an impure imipramine N-oxide preparation, and two of the impurities could be identified on the basis of online-MS(MS) spectra recorded in scan-dependent mode.     

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.     

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 new approach for analyzing particle motion near an interface using total internal reflection microscopy

A new method was developed for analyzing the normal motion of a single colloidal particle near an interface. The optical technique of total internal reflection microscopy (TIRM) was used to determine the distribution of vertical displacements of a particle from a specific starting position as a function of time. At very small displacement times, the displacements are normally distributed with a variance that is proportional to the diffusion coefficient times the displacement time. The change in the diffusion coefficient with separation distance between the particle and plate was found to match that predicted by Brenner (Chem. Eng. Sci. 16 (1961) 242). As the sampling time becomes very large, the variance reaches a constant value determined strictly by the shape of the local potential energy profile holding the particle. A major advantage of this approach, relative to other measurement methods, is that the particle's spatially variant diffusion coefficient can be determined without any knowledge of the forces acting on the particle.     

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.     

A universal interface for coupling mass spectrometry to thermogravimetry

Techniques for coupling mass spectrometry (MS) to thermogravimetry (TG) have been previously described. A total condensation method is best suited for identification of off-gases at various weight loss steps. For continuous monitoring of evolved components during the weight loss process, a glass-tee interface has been found effective in most applications. The present paper describes a glass tubing-tee interface used in conjunction with a sampler to provide great versatility. Both enrichment and recovery are improved without mass discrimination. The thermogravimetric analyzer can be operated under vacuum or with a gas flow. Examples will be given to illustrate the use of this technique for either qualitative or quantitative analysis of a variety of materials.     

Steric stabilization of spherical colloidal particles: Implicit and explicit solvent

We present the results of Monte Carlo simulations and density functional theory treatment of interactions between spherical colloidal brushes both in implicit (good) solvent and in an explicit polymeric solution. Overall, theory is seen to be in good agreement with simulations. We find that interactions between hard-sphere particles grafted with hard-sphere chains are always repulsive in implicit solvent. The range and steepness of the repulsive interaction is sensitive to the grafting density and the length of the grafted chains. When the brushes are immersed in an explicit solvent of hard-sphere chains, a weak mid-range attraction arises, provided the length of the free chains exceeds that of the grafted chains.