Effect of the environment on the stability of surfactant–polypeptide self‐assembled complexes: Molecular dynamics simulations of stoichiometric complexes formed by N‐dodecyltrimethylammonium and poly(α,L‐glutamate) in chloroform,methanol, and water

A series of molecular dynamics simulations have been performed to study the supramolecular structure of self‐assembled complexes formed by N‐dodecyltrimethylammonium cations and the synthetic polypeptide poly(α,L ‐glutamate). The influence of the type of solvent has been investigated, considering explicit environments of chloroform, water, and methanol on a stoichiometric complex containing 15 residues. In chloroform, the complex stabilizes in a regular structure: the polypeptide adopts an α‐helix conformation that is regularly surrounded by surfactant molecules to form electrostatic interactions through a multiple interaction pattern. However, this structure destabilizes in methanol and water: (a) the α‐helix unfolds in the two solvents and (b) the electrostatic links between the surfactant molecules and the polyanion are disrupted in aqueous solution, although these interactions are still preserved in methanol. The role of the solvent environment in stabilizing or destabilizing the polypeptide secondary structure, the organization of the surfactant molecules, and predominantly the surfactant–polypeptide supramolecular organization is discussed in detail. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 1122–1133, 2006     

Constant pH Molecular Dynamics in Explicit Solvent with λ-Dynamics

pH is an important parameter in condensed-phase systems, because it determines the protonation state of titratable groups and thus influences the structure, dynamics, and function of molecules in solution. In most force field simulation protocols, however, the protonation state of a system (rather than its pH) is kept fixed and cannot adapt to changes of the local environment. Here, we present a method, implemented within the MD package GROMACS, for constant pH molecular dynamics simulations in explicit solvent that is based on the λ-dynamics approach. In the latter, the dynamics of the titration coordinate λ, which interpolates between the protonated and deprotonated states, is driven by generalized forces between the protonated and deprotonated states. The hydration free energy, as a function of pH, is included to facilitate constant pH simulations. The protonation states of titratable groups are allowed to change dynamically during a simulation, thus reproducing average protonation probabilities at a certain pH. The accuracy of the method is tested against titration curves of single amino acids and a dipeptide in explicit solvent.     

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.     

Modeling and molecular dynamics simulation of the human gonadotropin-releasing hormone receptor in a lipid bilayer

In the present study, a model for the human gonadotropin-releasing hormone receptor embedded in an explicit lipid bilayer was developed. The final conformation was obtained by extensive molecular dynamics simulations of a homology model based on the bovine rhodopsin crystal structure. The analysis of the receptor structure allowed us to detect a number of specific contacts between different amino acid residues, as well as water- and lipid-mediated interactions. These interactions were stable in six additional independent 35 ns long simulations at 310 and 323 K, which used the refined model as the starting structure. All loops, particularly the extracellular loop 2 and the intracellular loop 3, exhibited high fluctuations, whereas the transmembrane helices were more static. Although other models of this receptor have been previously developed, none of them have been subjected to extensive molecular dynamics simulations, and no other three-dimensional structure is publicly available. Our results suggest that the presence of ions as well as explicit solvent and lipid molecules are critical for the structure of membrane protein models, and that molecular dynamics simulations are certainly useful for their refinement.     

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).     

Molecular simulation with variable protonation states at constant pH

A new method is presented for performing molecular simulations at constant pH. The method is a Monte Carlo procedure where trial moves consist of relatively short molecular dynamics trajectories, using a time-dependent potential energy that interpolates between the old and new protonation states. Conformations and protonation states are sampled from the correct statistical ensemble independent of the trial-move trajectory length, which may be adjusted to optimize efficiency. Because moves are not instantaneous, the method does not require the use of a continuum solvation model. It should also be useful in describing buried titratable groups that are not directly exposed to solvent, but have strong interactions with neighboring hydrogen bond partners. The feasibility of the method is demonstrated for a simple test case: constant-pH simulations of acetic acid in aqueous solution with an explicit representation of water molecules.     

New solvent for polyrotaxane. II. Dissolution behavior of polyrotaxane in ionic liquids and preparation of ionic liquid‐containing slide‐ring gels

The dissolution behavior of polyrotaxanes, consisting of α‐cyclodextrin and poly(ethylene glycol), with different molecular weights (2000 and 35,000) was investigated. Halogen‐containing ionic liquids, such as chlorides or bromides, were found to be good solvents for polyrotaxanes, regardless of their cations. Dissolution required a high temperature (above 90 °C), while intensive heating over 105 °C seemed to cause decomposition of the polyrotaxane. The discovery of new solvents for polyrotaxane was applied in the preparation of ionic liquid‐containing slide‐ring gels (SR gels), that is supramolecular networks of polyrotaxane swollen with ionic liquids, using a devised “non‐drying” technique accompanied by solvent exchange. Significant swelling of the SR gels with the ionic liquids was confirmed by dynamic mechanical measurements. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 1985–1994, 2006     

Solvent effects on electronic structures and chain conformations of alpha-oligothiophenes in polar and apolar solutions

Solvent effects on electronic structures and chain conformations of alpha-oligothiophenes nTs (n = 1 to 10) are investigated in solvents of n-hexane, 1,4-dioxane, carbon tetrachloride, chloroform, and water by using density functional theory (DFT) and molecular dynamics (MD) simulations. Both implicit and explicit solvent models are employed. The polarized continuum model (PCM) calculations and MD simulations demonstrate the weak solvent effects on the electronic structures of alpha-oligothiophenes. The lowest dipole-allowed vertical excitation energies of nTs, obtained from time-dependent DFT/PCM calculations at the B3LYP/6-31G(d) level, exhibit a red shift as the solvent polarity increases, in agreement with experiments. The studied solvents have little impact on the state order of the low-lying excited states provided that the nTs are kept in C2h or C2v symmetry. The MD simulations demonstrate that the chain conformations are distorted to some extent in polar and nonpolar solvents. A qualitative picture of the distribution of solvent molecules around the solvated nTs is drawn by means of radial and spatial distribution functions. The S...H-O and pi...H-O solute-solvent interactions are insignificant in aqueous solution.     

Monte Carlo study of the coil-to-globule transition of a model polymeric system

Monte Carlo computer simulations of single, flexible, self-avoiding chains on a cubic lattice have been performed upon conditions of increasing segment–segment cohesive energy (deteriorating solvent quality). The simulations spanned a wide range of chain lengths (20–10,000, i.e., up to molecular weights of a few millions) and cohesive energies (0.0–0.45k_BT, i.e., from athermal to very poor solvents). The chain length dependence of the chain size in poor solvents was characterized by a wide plateau of almost null growth for intermediate chain lengths. This plateau was linked to the development of the incipient constant density core, while genuine power law dependence (1/3) was not reached even for the longest chains and poorest solvents simulated here. The mere appearance of a core required substantial chain lengths (higher than 1000; molecular weights of a few hundred thousands), while short chains underwent a gradual densification devoid of any qualitative changes in the density distribution. Sufficiently long chains became more but not quite spherical and underwent a reasonably sharp second order phase transition. The findings were generally in agreement with predictions of mean-field theory and with the use of the standard scaling variables, despite slight inconsistencies. Nevertheless, the results stress the fact that short chains never form a constant density core and that core-dominance on the globule's properties (“volume approximation”) is only valid for extraordinarily long chains [molecular weight of O(10⁹)], an effect linked to the relatively diffuse nature of the surface layer and originating from chain connectivity in conjunction with spherical geometry. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 3651–3666, 2006     

Solvation of transmembrane proteins by isotropic membrane mimetics: a molecular dynamics study

Mixtures of organic solvents are often used as membrane mimetics in structure determination of transmembrane proteins by solution NMR; however, the mechanism through which these isotropic solvents mimic the anisotropic environment of cell membranes is not known. Here, we use molecular dynamics simulations to study the solvation thermodynamics of the c-subunit of Escherichia coli F1F0 ATP synthase in membrane mimetic mixtures of methanol, chloroform, and water with varying fractions of components as well as in lipid bilayers. We show that the protein induces a local phase separation of the solvent components into hydrophobic and hydrophilic layers, which provides the anisotropic solvation environment to stabilize the amphiphilic peptide. The extent of this effect varies with solvent composition and is most pronounced in the ternary methanol-chloroform-water mixtures. Analysis of the solvent structure, including the local mole fraction, density profiles, and pair distribution functions, reveals considerable variation among solvent mixtures in the solvation environment surrounding the hydrophobic transmembrane region of the protein. Hydrogen bond analysis indicates that this is primarily driven by the hydrogen-bonding propensity of the essential Asp(61) residue. The impact of the latter on the conformational stability of the solvated protein is discussed. Comparison with the simulations in explicit all-atom models of lipid bilayer indicates a higher flexibility and reduced structural integrity of the membrane mimetic solvated c-subunit. This was particularly true for the deprotonated form of the protein and found to be linked to solvent stabilization of the charged Asp(61).     

Accurate prediction of protonation state as a prerequisite for reliable MM-PB(GB)SA binding free energy calculations of HIV-1 protease inhibitors

Binding free energies were calculated for the inhibitors lopinavir, ritonavir, saquinavir, indinavir, amprenavir, and nelfinavir bound to HIV-1 protease. An MMPB/SA-type analysis was applied to conformational samples from 3 ns explicit solvent molecular dynamics simulations of the enzyme-inhibitor complexes. Binding affinities and the sampled conformations of the inhibitor and enzyme were compared between different HIV-1 protease protonation states to find the most likely protonation state of the enzyme in the complex with each of the inhibitors. The resulting set of protonation states leads to good agreement between calculated and experimental binding affinities. Results from the MMPB/SA analysis are compared with an explicit/implicit hybrid scheme and with MMGB/SA methods. It is found that the inclusion of explicit water molecules may offer a slight advantage in reproducing absolute binding free energies while the use of the Generalized Born approximation significantly affects the accuracy of the calculated binding affinities.     

Solvation of Co(III)-cysteinato complexes in water: a DFT-based molecular dynamics study

Structural, dynamical, and vibrational properties of complexes made of metal cobalt(III) coordinated to different amounts of cysteine molecules were investigated with DFT-based Car-Parrinello molecular dynamics (CPMD) simulations in liquid water solution. The systems are composed of Co(III):3Cys and Co(III):2Cys immersed in liquid water which are modeled by about 110 explicit water molecules, thus one of the biggest molecular systems studied with ab initio molecular simulations so far. In such a way, we were able to investigate structural and dynamical properties of a model of a typical metal binding site used by several proteins. Cobalt, mainly a toxicological agent, can replace the natural binding metal and thus modify the biochemical activity. The structure of the surrounding solvent around the metal-ligands complexes is reported in detail, as well as the metal-ligands coordination bonds, using radial distribution functions and electronic analyses with Mayer bond orders. Structures of the Cocysteine complexes are found in very good agreement with EXAFS experimental data, stressing the importance of considering the surrounding solvent in the modeling. A vibrational analysis is also conducted and compared to experiment, which strengthens the reliability of the solvent interactions with the Cocysteine complexes from our molecular dynamics simulations, as well as the dynamics of the systems. From this preliminary analysis, we could suggest a vibrational fingerprint able to distinguish Co(III):2Cys from Co(III):3Cys. Our simulations also show the importance of considering a quantum explicit solvent, as solute-to-solvent proton transfer events have been observed.     

A generalized Langevin dynamics approach to model solvent dynamics effects on proteins via a solvent-accessible surface. The carboxypeptidase A inhibitor protein as a model

A generalized Langevin dynamics (GLD) scheme is derived for (bio)macromolecules having internal structure, arbitrary shapes and a size larger than solvent molecules (i.e. proteins). The concept of solvent-accessible surface area (SASA) is used to incorporate solvent effects via external forces thereby avoiding its explicit molecular representation. A simulation algorithm is implemented in the GROMOS molecular dynamics (MD) program including random forces and memory effects, while solvation effects enter via derivatives of the surface area. The potato carboxypeptidase inhibitor (PCI), a small protein, is used to numerically test the approach. This molecule has N- and C-terminal tails whose structure and fluctuations are solvent dependent. A 1-ns MD trajectory was analyzed in depth. X-ray and NMR structures are used in conjunction with MD simulations with and without explicit solvent to gauge the quality of the results. All the analyses showed that the GLD simulation approached the results obtained for the MD simulation with explicit simple-point-charge-model water molecules. The SASAs of the polar atoms show a natural exposure towards the solvent direction. A FLS solvent simulation was completed in order to sense memory effects. The approach and results presented here could be of great value for developing alternatives to the use of explicit solvent molecules in the MD simulation of proteins, expanding its use and the time-scale explored. Received: 2 February 2000 / Revised: 12 March 2000 / Accepted: 26 May 2000 / Published online: 2 November 2000     

Phase separation in binary mixtures containing polymers: A quantitative comparison of single-chain-in-mean-field simulations and computer simulations of the corresponding multichain systems

We discuss a phenomenological, coarse-grained simulation scheme, single-chain-in-mean-field (SCMF) simulation, for investigating the kinetics of phase separation in dense polymer blends and mixtures of polymers and solvents. In the spirit of self-consistent-field calculations, we approximate the interacting multichain problem by that of a single chain in an external field, which, in turn, depends on the local densities of the components. To study the time evolution of the mixture, we perform an explicit Monte Carlo (MC) simulation of an ensemble of independent chains in the external field and periodically calculate the average densities and update the external field. Unlike dynamic self-consistent-field theory, these SCMF simulations do not assume that the chain conformations relax much more quickly than the density and incorporate the single-chain dynamics explicitly rather than via an Onsager coefficient. This allows us to study systems with large spatial inhomogeneities and dynamic asymmetries. To assess the accuracy and limitations of the simulation scheme, we compare the results of SCMF simulations using a discretized Edwards Hamiltonian with computer simulations of the corresponding multichain system for (1) the early stages of spinodal decomposition of a symmetric binary polymer blend in response to a quench from χN = 0.314 to χN = 5 (where χ is the Flory–Huggins parameter and N is the number of segments), for which the growth rate of composition fluctuations is compared with MC simulations of the bond fluctuation model and alternative dynamic self-consistent-field calculations, and (2) the evaporation of a solvent from a low-molecular-weight thin polymer film, for which a comparison is made with molecular dynamics (MD) simulations of a bead-necklace model with a monomeric solvent. In the latter case, the polymer conformations are extracted from MD simulations and modeled in the SCMF simulations by a discretized Edwards Hamiltonian augmented by a chain-bending potential. From the MD simulations of thin polymer films in equilibrium with its vapor, phase coexistence has been determined, and the second- and third-order virial coefficients in the SCMF simulations have been adjusted accordingly. Finally, MD simulations of bulk solutions of a polymer and a solvent over a range of compositions, as well as the pure solvent at various densities, have been performed to determine self-diffusion coefficients that enter the SCMF simulations in the form of density-dependent segmental mobilities. A comparison of the polymer and solvent profiles in a thin film as a function of time and the fraction of the solvent evaporating from a solvent-swollen film, as obtained from MD simulations and parameterized SCMF simulations, shows satisfactory agreement for this simple mapping procedure. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 934–958, 2005     

Heats of protonation of amines,diazacrown ethers and cryptands in methanol

The heats of protonation of different amines, diazacrown ethers and cryptands in methanol have been measured using calorimetric titrations. The values of the reaction enthalpies decrease in going from primary over secondary to tertiary amines. The results for the protonation of diazacrown ethers and cryptands are not comparable with those obtained for the alkyl amines. Additional interactions between the proton and the oxygen donor atoms influence the values of the reaction enthalpy for the first protonation. The results for the second protonation reaction indicate that this proton is located outside the cavities of the macrocyclic and macrobicyclic ligands. This revised version was published online in July 2006 with corrections to the Cover Date.     

Titanium‐mediated living radical styrene polymerizations. V. Cp2TiCl‐catalyzed initiation by epoxide radical ring opening: Effect of solvents and additives

The effects of solvents, additives, ligands, and solvent in situ drying agents as well as catalyst and initiator concentrations have been investigated in the Cp₂TiCl‐catalyzed radical polymerization of styrene initiated by epoxide radical ring opening. On the basis of the solubilization of Cp₂Ti(III)Cl and the polydispersity of the resulting polymer, the solvents rank as follows: dioxane ≥ tetrahydrofuran > diethylene glycol dimethyl ether > methoxybenzene > diphenyl ether ≥ bulk > toluene ? pyridine > dimethylformamide > 1‐methyl‐2‐pyrrolidinone > dimethylacetamide > ethylene carbonate, acetonitrile, and trioxane. Alkoxide additives such as aluminum triisopropoxide and titanium(IV) isopropoxide are involved in alkoxide ligand exchange with the epoxide‐derived titanium alkoxide and lead to broad molecular weight distributions, whereas similarly to strongly coordinating solvents, ligands such as bipyridyl block the titanium active site and prevent the polymerization. By contrast, softer ligands such as triphenylphosphine improve the polymerization in less polar solvents such as toluene. Although mixed hydrides such as lithium tri‐tert‐butoxyaluminum hydride, sodium borohydride, and lithium aluminum hydride react with bis(cyclopentadienyl)titanium dichloride to form mixed titanium hydride species ineffective in polymerization control, simple hydrides such as lithium hydride, sodium hydride, and especially calcium hydride are particularly effective as in situ trace water scavengers in this polymerization. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 2015–2026, 2006     

Theoretical study of the effects of solvent environment on photophysical properties and electronic structure of paracyclophane chromophores

We use first-principles quantum-chemical approaches to study absorption and emission properties of recently synthesized distyrylbenzene (DSB) derivative chromophores and their dimers (two DSB molecules linked through a [2.2]paracyclophane moiety). Several solvent models are applied to model experimentally observed shifts and radiative lifetimes in Stokes nonpolar organic solvents (toluene) and water. The molecular environment is simulated using the implicit solvation models, as well as explicit water molecules and counterions. Calculations show that neither implicit nor explicit solvent models are sufficient to reproduce experimental observations. The contact pair between the chromophore and counterion, on the other hand, is able to reproduce the experimental data when a partial screening effect of the solvent is taken into account. Based on our simulations we suggest two mechanisms for the excited-state lifetime increase in aqueous solutions. These findings may have a number of implications for organic light-emitting devices, electronic functionalities of soluble polymers and molecular fluorescent labels, and their possible applications as biosensors and charge/energy conduits in nanoassemblies.     

A calculation of the relative protonation energies of amines in solution

Relative protonation energies in the primary, secondary and tertiary aliphatic series of amines are calculated by a semiempirical method employing the virtual charge model. The method accounts quite well for the observed differences between the gas-phase protonation affinities and the protonation enthalpies in solution, but when allowance is made for steric shielding from the bulk solvent for “non-edge” atoms, some anomalies in the uncorrected model are removed. The calculated solute-solvent interactions are related to experimental enthalpies of solution and to trends expected from the Born model.     

Versatile and controlled synthesis of resorbable star‐shaped polymers using a spirocyclic tin initiator—Reaction optimization and kinetics

A spirocyclic tin initiator was synthesized from pentaerythritol ethoxylate and dibutyltin oxide and used to polymerize L ‐lactide with dichloromethane, chloroform, toluene, and chlorobenzene as solvents. The reactions were performed at different temperatures and it is concluded that neither the temperature nor the solvent affects the molecular weight or the molecular weight distribution of the star‐shaped polymers. The reaction rate was significantly increased by raising the reaction temperature or choosing a solvent with a low dielectric constant. All polymers showed a molecular‐weight distribution below 1.19 and a molecular‐weight determined by the initial monomer to initiator concentration ([M]₀/[I]). No induction period was seen for the polymerizations. They were all first order in initiator and the degree of aggregation in toluene at 110 °C was found to be 4/5. The glass transition temperature and the melting temperature of the star‐shaped polymers increase with increasing arm length. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 596–605, 2006