Molecular dynamics simulations of spontaneous bile salt aggregation

Bile salts are surfactants in bile that facilitate digestion, adsorption and excretion of various compounds. They have planar hydrophobic and hydrophilic faces and therefore exhibit some unusual properties; including the shape and size of the micelles that they form. Molecular dynamics simulations of the spontaneous aggregation of six bile salts (cholate (CHD), glycocholate (GCH), taurocholate (TCH), glycochenodeoxycholate (GCD), glycodeoxycholate (GDX) and glycolithocholate (GLC)) were performed in an aqueous phase to gain insight into their micellar structure. The aggregates that formed spontaneously from a random distribution of molecules ranged in size from 8 to 17 molecules. The structures are highly dynamic in nature and are on average oblate, but can vary from oblate, to spherical or prolate. Intermolecular hydrogen bonding within the micelles was found to be an important factor in determining the micelle size, structure and dynamics. The molecular arrangement within the micelles maximises the hydration of the hydrophilic chains and some favourable orientations for adjacent molecules were acquired. The dynamics of the micelles were investigated using the hydrogen-bond lifetime autocorrelation function correlation time, which exhibited a relationship with the degree of hydroxylation. Comparison of the proposed model to the three literature models showed some features of the disk shaped models of Cary and Small [M.C. Cary, D.M. Small, Arch. Intern. Med. 130 (1972) 506–527] and Kawamura et al. [H. Kawamura, Y. Murata, T. Yamaguchi, H. Igimi, M. Tanaka, G. Sugihara, J.P. Kratohvil, J. Phys. Chem. 93 (1989) 3321–3326], whereas the third, inverted helix model of Giglio et al. [E. Giglio, S. Loreti, N.V. Pavel, J. Phys. Chem. 92 (1988) 2858–2862] can be discounted. The proposed model is better than the existing models, which assumed a rigid and structured molecular arrangement.     

Molecular dynamics simulations of beta-cyclodextrin-aziadamantane complexes in water

Force-field-based atomistic simulations of host-guest supramolecular complexes between beta-cyclodextrin and several aziadamantane derivatives have been analyzed with respect to relative orientation and interaction energies, explicitly considering solvent (water) molecules. For each case, the calculations revealed two stable orientations of the guest within the host that are different in interaction energy. Fluctuation of and correlation between characteristic properties were analyzed. Among other things, it turned out that orientation angle and inclusion depth are clearly correlated. In addition, for the unsubstituted aziadamantane, the enthalpy of complex formation was calculated and compared to experimental results.     

Molecular dynamics simulations of dendritic polyelectrolytes with flexible spacers in salt free solution

We present the results of molecular dynamics simulations of dendritic polyelectrolytes in dilute salt-free solutions. The dendritic polyelectrolytes are modeled as an ensemble of regular-branched bead-spring chains of neutral and charged Lennard-Jones particles with explicit counterions. A wide range of molecular variables of the dendritic polyelectrolytes such as generation number, spacer length, and charge density were considered in the simulations. The effect of dendrimer size on relaxation time, the conformation of spacers, and the size dependence of the dendrimer on molecular variables are discussed and compared with a Flory type theory. The osmotic coefficients of the dilute dendritic polyelectrolyte solutions, as well as the profiles of monomers and counterions, are calculated directly from the simulations. Our simulation results show that the inner spacers of the dendrimers are extensively stretched, and the size dependence on the molecular weight deviates from the scaling prediction that assumes a Gaussian elasticity of the spacer.     

Denaturation of Drew-Dickerson DNA in a high salt concentration medium: molecular dynamics simulations

We have performed molecular dynamics simulation on B-DNA duplex (CGCGAATTGCGC) at different temperatures. The DNA was immerged in a salt-water medium with 1 M NaCl concentration to investigate salt effect on the denaturation process. At each temperature, configurational entropy is estimated using the covariance matrix of atom-positional fluctuations, from which the melting temperature (T(m)) was found to be 349 K. The calculated configuration entropy for different bases shows that the melting process involves more peeling (including fraying from the ends) conformations, and therefore the untwisting of the duplex and peeling states form the transition state of the denaturation process. There is a narrow minor groove in the AATT sequence that becomes wider by increasing temperature which disappears at high temperatures, especially above the melting temperature. We have also calculated the fraction of denatured base pairs, f-curve, from which T(m) was found to be 340 K, close to experimental value of 341 K. We found that DNA at high salt concentrations has few hydrogen bonds even at temperatures higher than the T(m). Our calculations show the fact that adding salt leads to increase of T(m) and stabilization of DNA.     

Polymer brushes in solvents of variable quality: molecular dynamics simulations using explicit solvent

The structure and thermodynamic properties of a system of end-grafted flexible polymer chains grafted to a flat substrate and exposed to a solvent of variable quality are studied by molecular dynamics methods. The macromolecules are described by a coarse-grained bead-spring model, and the solvent molecules by pointlike particles, assuming Lennard-Jones-type interactions between pairs of monomers (epsilon(pp)), solvent molecules (epsilon(ss)), and solvent monomer (epsilon(ps)), respectively. Varying the grafting density sigma(g) and some of these energy parameters, we obtain density profiles of solvent particles and monomers, study structural properties of the chain (gyration radius components, bond orientational parameters, etc.), and examine also the profile of the lateral pressure P( parallel)(z), keeping in the simulation the normal pressure P( perpendicular) constant. From these data, the reduction of the surface tension between solvent and wall as a function of the grafting density of the brush has been obtained. Further results include the stretching force on the monomer adjacent to the grafting site and its variation with solvent quality and grafting density, and dynamic characteristics such as mobility profiles and chain relaxation times. Possible phase transitions (vertical phase separation of the solvent versus lateral segregation of the polymers into "clusters," etc.) are discussed, and a comparison to previous work using implicit solvent models is made. The variation of the brush height and the interfacial width of the transition zone between the pure solvent and the brush agrees qualitatively very well with corresponding experiments.     

Molecular dynamics simulations of halide glasses

Summary Halide glasses have been extensively studied in recent years because of their potential application as infrared transmitting fibre optic materials. They are believed to be more ionic than glasses based on silica and should therefore be more amenable to molecular dynamics simulation using simple two-body potentials. Here the main features of structural models derived using such techniques are described and compared with available structural data. Possible future applications of this approach are outlined.     

Molecular dynamics simulations of peptide-surface interactions

Proteins, which are bioactive molecules, adsorb on implants placed in the body through complex and poorly understood mechanisms and directly influence biocompatibility. Molecular dynamics modeling using empirical force fields provides one of the most direct methods of theoretically analyzing the behavior of complex molecular systems and is well-suited for the simulation of protein adsorption behavior. To accurately simulate protein adsorption behavior, a force field must correctly represent the thermodynamic driving forces that govern peptide residue-surface interactions. However, since existing force fields were developed without specific consideration of protein-surface interactions, they may not accurately represent this type of molecular behavior. To address this concern, we developed a host-guest peptide adsorption model in the form of a G(4)-X-G(4) peptide (G is glycine, X is a variable residue) to enable determination of the contributions to adsorption free energy of different X residues when adsorbed to functionalized Au-alkanethiol self-assembled monolayers (SAMs). We have previously reported experimental results using surface plasmon resonance (SPR) spectroscopy to measure the free energy of peptide adsorption for this peptide model with X = G and K (lysine) on OH and COOH functionalized SAMs. The objectives of the present research were the development and assessment of methods to calculate adsorption free energy using molecular dynamics simulations with the GROMACS force field for these same peptide adsorption systems, with an oligoethylene oxide (OEG) functionalized SAM surface also being considered. By comparing simulation results to the experimental results, the accuracy of the selected force field to represent the behavior of these molecular systems can be evaluated. From our simulations, the G(4)-G-G(4) and G(4)-K-G(4) peptides showed minimal to no adsorption to the OH SAM surfaces and the G(4)-K-G(4) showed strong adsorption to the COOH SAM surface, which is in agreement with our SPR experiments. Contrary to our experimental results, however, the simulations predicted a relatively strong adsorption of G(4)-G-G(4) peptide to the COOH SAM surface. In addition, both peptides were unexpectedly predicted to adsorb to the OEG surface. These findings demonstrate the need for GROMACS force field parameters to be rebalanced for the simulation of peptide adsorption behavior on SAM surfaces. The developed methods provide a direct means of assessing, modifying, and validating force field performance for the simulation of peptide and protein adsorption to surfaces, without which little confidence can be placed in the simulation results that are generated with these types of systems.     

Molecular dynamics simulations of cardiolipin bilayers

Cardiolipin is a key lipid component in the inner mitochondrial membrane, where the lipid is involved in energy production, cristae structure, and mechanisms in the apoptotic pathway. In this article we used molecular dynamics computer simulations to investigate cardiolipin and its effect on the structure of lipid bilayers. Three cardiolipin/POPC bilayers with different lipid compositions were simulated: 100, 9.2, and 0% cardiolipin. We found strong association of sodium counterions to the carbonyl groups of both lipid types, leaving in the case of 9.2% cardiolipin virtually no ions in the aqueous compartment. Although binding occurred primarily at the carbonyl position, there was a preference to bind to the carbonyl groups of cardiolipin. Ion binding and the small headgroup of cardiolipin gave a strong ordering of the hydrocarbon chains. We found significant effects in the water dipole orientation and water dipole potential which can compensate for the electrostatic repulsion that otherwise should force charged lipids apart. Several parameters relevant for the molecular structure of cardiolipin were calculated and compared with results from analyses of coarse-grained simulations and available X-ray structural data.     

Molecular dynamics simulations of biotin carboxylase

Biotin carboxylase catalyzes the ATP-dependent carboxylation of biotin and is one component of the multienzyme complex acetyl-CoA carboxylase that catalyzes the first committed step in fatty acid synthesis in all organisms. Biotin carboxylase from Escherichia coli, whose crystal structures with and without ATP bound have been determined, has served as a model system for this component of the acetyl-CoA carboxylase complex. The two crystal structures revealed a large conformational change of one domain relative to the other domains when ATP is bound. Unfortunately, the crystal structure with ATP bound was obtained with an inactive site-directed mutant of the enzyme. As a consequence the structure with ATP bound lacked key structural information such as for the Mg2+ ions and contained altered conformations of key active-site residues. Therefore, nanosecond molecular dynamics studies of the wild-type biotin carboxylase were undertaken to supplant and amend the results of the crystal structures. Specifically, the protein-metal interactions of the two catalytically critical Mg2+ ions bound in the active site are presented along with a reevaluation of the conformations of active-site residues bound to ATP. In addition, the regions of the polypeptide chain that serve as hinges for the large conformational change were identified. The results of the hinge analysis complemented a covariance analysis that identified the individual structural elements of biotin carboxylase that change their conformation in response to ATP binding.     

Molecular dynamics simulations of polyelectrolyte adsorption

We have performed molecular dynamics simulations of polyelectrolyte adsorption at oppositely charged surfaces from dilute polyelectrolyte solutions. In our simulations, polyelectrolytes were modeled by chains of charged Lennard-Jones particles with explicit counterions. We have studied the effects of the surface charge density, surface charge distribution, solvent quality for the polymer backbone, strength of the short-range interactions between polymers and substrates on the polymer surface coverage, and the thickness of the adsorbed layer. The polymer surface coverage monotonically increases with increasing surface charge density for almost all studied systems except for the system of hydrophilic polyelectrolytes adsorbing at hydrophilic surfaces. In this case the polymer surface coverage saturates at high surface charge densities. This is due to additional monomer-monomer repulsion between adsorbed polymer chains, which becomes important in dense polymeric layers. These interactions also preclude surface overcharging by hydrophilic polyelectrolytes at high surface charge densities. The thickness of the adsorbed layer shows monotonic dependence on the surface charge density for the systems of hydrophobic polyelectrolytes for both hydrophobic and hydrophilic surfaces. Thickness is a decreasing function of the surface charge density in the case of hydrophilic surfaces while it increases with the surface charge density for hydrophobic substrates. Qualitatively different behavior is observed for the thickness of the adsorbed layer of hydrophilic polyelectrolytes at hydrophilic surfaces. In this case, thickness first decreases with increasing surface charge density, then it begins to increase.     

Molecular dynamics simulations of lipid bilayers

Computer simulation methods are becoming increasingly widespread as tools for studying the structure and dynamics of lipid bilayer membranes. The length scale and time scale accessible to atomic-level molecular dynamics simulations are rapidly increasing, providing insight into the relatively slow motions of molecular reorientation and translation and demonstrating that effects due to the finite size of the simulation cell can influence simulation results. Additionally, significant advances have been made in the complexity of membrane systems studied, including bilayers with cholesterol, small solute molecules, and lipid-protein and lipid-DNA complexes. Especially promising is the progress that continues to be made in the comparison of simulation results with experiment, both to validate the simulation algorithms and to aid in the interpretation of existing experimental data.     

Calculations of solute and solvent entropies from molecular dynamics simulations

The translational, rotational and conformational (vibrational) entropy contributions to ligand-receptor binding free energies are analyzed within the standard formulation of statistical thermodynamics. It is shown that the partitioning of the binding entropy into different components is to some extent arbitrary, but an appropriate method to calculate both translational and rotational entropy contributions to noncovalent association is by estimating the configurational volumes of the ligand in the bound and free states. Different approaches to calculating solute entropies using free energy perturbation calculations, configurational volumes based on root-mean-square fluctuations and covariance matrix based quasiharmonic analysis are illustrated for some simple molecular systems. Numerical examples for the different contributions demonstrate that theoretically derived results are well reproduced by the approximations. Calculation of solvent entropies, either using total potential energy averages or van't Hoff plots, are carried out for the case of ion solvation in water. Although convergence problems will persist for large and complex simulation systems, good agreement with experiment is obtained here for relative and absolute ion hydration entropies. We also outline how solvent and solute entropic contributions are taken into account in empirical binding free energy calculations using the linear interaction energy method. In particular it is shown that empirical scaling of the nonpolar intermolecular ligand interaction energy effectively takes into account size dependent contributions to the binding free energy.     

Molecular dynamics of cryptophane and its complexes with tetramethylammonium and neopentane using a continuum solvent model

Time scales currently obtainable in explicit–solvent molecular dynamics simulations are inadequate for the study of many biologically important processes. This has led to increased interest in the use of continuum solvent models. For such models to be used effectively, it is important that their behavior relative to explicit simulation be clearly understood. Accordingly, 5 ns stochastic dynamics simulations of a derivative of cryptophane-E alone, and complexed with tetramethylammonium and neopentane were carried out. Solvation electrostatics were accounted for via solutions to the Poisson equation. Nonelectrostatic aspects of solvation were incorporated using a surface area-dependent energy term. Comparison of the trajectories to those from previously reported 25 ns explicit–solvent simulations shows that use of a continuum solvent model results in enhanced sampling. Use of the continuum solvent model also results in a considerable increase in computational efficiency. The continuum solvent model is found to predict qualitative structural characteristics that are similar to those observed in explicit solvent. However, some differences are significant, and optimization of the continuum parameterization will be required for this method to become an efficient alternative to explicit–solvent simulation. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 956–970, 1999     

Brownian dynamics simulations of polyelectrolyte adsorption in shear flow: effects of solvent quality and charge patterning

We probe the effects of solvent quality and charge patterning on polyelectrolyte adsorption in shear flow using Brownian dynamics simulations with hydrodynamic interaction (HI). The polyelectrolyte is modeled as a freely jointed bead-rod chain, and electrostatic and non-electrostatic interactions are accounted for by using screened Coulombic and Lennard-Jones potentials, respectively. In the absence of flow, the conformation of a polyelectrolyte molecule adsorbed onto a uniformly charged surface changes from flat to globular with an increase in bead-bead attraction (hydrophobicity), consistent with prior experimental observations. In the presence of flow, migration due to bead-wall HI and, as a consequence, desorption decrease with an increase in bead-bead attraction, implying that flow-induced desorption is more difficult under poor-solvent conditions. When bead-bead non-electrostatic attraction is strong, desorption can be enhanced by increasing bead-bead electrostatic repulsion. Analogous to the effect of bead-surface electrostatic attraction, an increase in the strength of bead-surface non-electrostatic attraction reduces desorption. We also study the effect of shear flow on the adsorption of a polyelectrolyte molecule onto surfaces decorated with periodic arrays of charged patches. An increase in patch periodicity increases desorption even when the effective surface charge density is kept the same. The results of this work suggest mechanisms for controlling the desorption of polyelectrolyte molecules in shear flows.     

Modeling solvent effects in molecular dynamics simulations of proteins

A series of computer simulations has been carried out on bovine pancreatic trypsin inhibitor using various models to mimic the effects of explicit bulk solvent on the structure of the protein. The solvent properties included are the polarization of the solute by the polar bulk solvent and the restraining effect on the motional freedom of the solute due to frictional drag at the solvent–protein surface interface. The former has been included by using a distance–dependent dielectric permittivity to screen the electrostatic interactions, whereas the latter is simulated by adding a limited number of solvent molecules near the protein surface. To achieve the proper mobility of the water molecules, their motion was restrained by adding a harmonic restraining force. It was found that a very small force constant was sufficient to model the static and dynamical behavior of the fully solvated solute, but that it was necessary to include enough explicit waters to occupy the first solvation shell. © 1992 John Wiley & Sons, Inc.     

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.     

Molecular dynamics simulations of pressure effects on hydrophobic interactions.

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