alpha-, beta-, and gamma-Cyclodextrin dimers. Molecular modeling studies by molecular mechanics and molecular dynamics simulations.

The alpha-, beta-, and gamma-cyclodextrin (CyD) dimers have been studied by molecular mechanics (MM) and molecular dynamics (MD) calculations, and the relative stability of dimers and the involved molecular interactions have been determined. Three possible orientations were considered for the alpha-, beta-, and gamma-CyD dimers: the head-to-head, the head-to-tail, and the tail-to-tail. In vacuo MM calculations were used to obtain the most stable arrangements, and MD simulations were performed over all energy minima obtained for each dimer. Results from MD always show head-to-head orientation as the most stable as a result of the larger number of intermolecular hydrogen bonds present.     

Complexation behavior of alpha-, beta-, and gamma-cyclodextrin in modulating and constructing polymer networks

A systematic study of the host-guest complexation by alpha-, beta-, and gamma-cyclodextrin (CD) in either the free state or as substituents of poly(acrylic acid) (PAA) with the hydrophobic n-octadecyl groups, C18, substituted onto PAA (HMPAA) and its effect on polymer aggregation and network formation is reported. Free alpha-CD, beta-CD, and gamma-CD mask hydrophobic associations between the C18 substituent of HMPAA in aqueous solution and form host-guest complexes with a 1:1 or CD:C18 substituent stoichiometry at 0.5 wt % polymer concentration. For alpha-CD this host-guest stoichiometry changes to 2:1 or 2alpha-CD:C18 at > or =1 wt % polymer concentrations but not for beta-CD and gamma-CD. Shear-thickening occurs when gamma-CD complexes C18 HMPAA substituents. Upon addition of sodium dodecyl sulfate, SDS (SDS:CD = 1:1), the hydrophobic associations between C18 diminished by alpha-CD masking were fully restored, were only partly restored in the case of beta-CD, and not restored for gamma-CD. When alpha- and beta-CD substituted PAA (alpha-CDPAA and beta-CDPAA) were mixed with HMPAA polymer, networks formed. As for free beta-CD, the beta-CD substituents of beta-CDPAA also formed 1:1 or beta-CD:C18 stoichiometry host-guest complexes with the C18 substituents of HMPAA. The alpha-CD substituents of alpha-CDPAA also formed 1:1 or alpha-CD:C18 stoichiometry host-guest complexes with some indication of the formation of 2:1 or 2alpha-CD:C18 stoichiometry host-guest complexes at polymer concentrations > or =1 wt %. The polymer networks formed by beta-CDPAA with HMPAA are less viscous than those formed by alpha-CDPAA, for which shear-thickening occurs at polymer concentrations > or =2 wt %. It is evident that the difference in CD annular size and its match with the C18 of HMPAA control the diversity of the interactions of alpha-CD, beta-CD, gamma-CD, alpha-CDPAA, and beta-CDPAA with HMPAA.     

Molecular recognition thermodynamics of bile salts by beta-cyclodextrin dimers: Factors governing the cooperative binding of cyclodextrin dimers

The complex stability constants (K(S)), standard molar enthalpy (DeltaH degrees), and entropy changes (DeltaS degrees) for the inclusion complexation of two families of beta-cyclodextrin (beta-CD) dimers, i.e. beta-CD dimers Se1-Se4 bearing 2,2'-diselenobis(benzoyl) tether (Se-dimers) and beta-CD dimers Py1-Py4 bearing 2,2'-bipyridine-4,4'-dicarboxy tether (Py-dimers), with four bile salt guests, i.e. sodium cholate (CA), sodium deoxycholate (DCA), sodium glycocholate (GCA), and sodium taurocholate (TCA), were determined at 25 degrees C in Tris buffer solution (pH 7.4) at 298.15 K by means of isothermal titration microcalorimetry. The thermodynamic parameters obtained, together with the ROESY spectra of interactions between beta-CD dimers and bile salts, consistently suggest that the length, flexibility, and structure of spacers linking the two beta-CD cavities not only determine the binding modes but also significantly alter the molecular selectivity of beta-CD dimers.     

Glucose orientation and dynamics in alpha-, beta-, and gamma-cyclodextrins

We investigate, using molecular dynamics (MD) computer simulations, the conformational behavior of alpha-, beta-, and gamma-cyclodextrins (CDs). Our analysis of a 30 ns trajectory of CD solution dynamics reveals the underlying conformational behaviours of the CDs that explain their relative flexibility. The distributions of the torsion angles related to the glycosidic linkages, P(phi,psi) were calculated for the three CDs. Most noticeable is the limited range in phi torsion rotations compared with psi rotations for all the CDs. This difference between the three CDs is amplified in the motion and dynamics of their glucose monomers when we monitor their orientational and librational positions relative to the macrocyclic mean plane. The relaxation times of the monomers to their equilibrium orientations follow the pattern gamma-CD > alpha-CD > beta-CD. The root-mean-square deviations of the motion of the monomer centers of mass from the mean macrocyclic planes exhibit the same trend.     

Calculation of ligand binding free energies from molecular dynamics simulations

A recently developed method for predicting binding affinities in ligand–receptor complexes, based on interaction energy averaging and conformational sampling by molecular dynamics simulation, is presented. Polar and nonpolar contributions to the binding free energy are approximated by a linear scaling of the corresponding terms in the average intermolecular interaction energy for the bound and free states of the ligand. While the method originally assumed the validity of electrostatic linear response, we show that incorporation of systematic deviations from linear response derived from free energy perturbation calculations enhances the accuracy of the approach. The method is applied to complexes of wild-type and mutant human dihydrofolate reductases with 2,4-diaminopteridine and 2,4-diaminoquinazoline inhibitors. It is shown that a binding energy accuracy of about 1 kcal/mol is attainable even for multiply ionized compounds, such as methotrexate, for which electrostatic interactions energies are very large. © 1998 John Wiley & Sons, Inc. Int J Quant Chem 69: 77–88, 1998     

Molecular electrostatic potentials and hydrogen bonding in alpha-, beta-, and gamma-cyclodextrins

Cyclodextrins (CDs) are cyclic oligomers of glucose having the toroid of sugars elaborating a central cavity of varying size depending on the number of glucoses. The central hydrophobic cavity of CD shows a binding affinity toward different guest molecules, which include small substituted benzenes to long chain surfactant molecules leading to a variety of inclusion complexes when the size and shape complementarity of host and guest are compatible. Further, interaction of guest molecules with the outer surface of alpha-CD has also been observed. Primarily it is the electrostatic interactions that essentially constitute a driving force for the formation of inclusion complexes. To gain insights for these interactions, the electronic structure and the molecular electrostatic potentials in alpha-, beta-, and gamma-CDs are derived using the hybrid density functional theory employing the three-parameter exchange correlation functional due to Becke, Lee, Yang, and Parr (B3LYP). The present work demonstrates how the topography of the molecular electrostatic potential (MESP) provides a measure of the cavity dimensions and understanding of the hydrogen-bonded interactions involving primary and secondary hydroxyl groups. In alpha-CD, hydrogen-bonded interactions between primary -OH groups engender a "cone-like" structure, while in beta- or gamma-CD the interactions from the primary -OH with ether oxygen in glucose ring facilitates a "barrel-like" structure. Further, the strength of hydrogen-bonded interactions of primary -OH groups follows the rank order alpha-CD > beta-CD > gamma-CD, while the secondary hydrogen-bonded interactions exhibit a reverse trend. Thus weak hydrogen-bonded interactions prevalent in gamma-CD manifest in shallow MESP minima near hydroxyl oxygens compared to those in alpha- or beta-CD. Furthermore, electrostatic potential topography reveals that the guest molecule tends to penetrate inside the cavity forming the inclusion complex in beta- or gamma-CD.     

Solvent and guest isotope effects on complexation thermodynamics of alpha-, beta-, and 6-amino-6-deoxy-beta-cyclodextrins

The stability constant (K), standard free energy (DeltaG degrees ), enthalpy (DeltaH degrees ), and entropy changes (TDeltaS degrees ) for the complexation of native alpha- and beta-cyclodextrins (CDs) and 6-amino-6-deoxy-beta-CD with more than 30 neutral, positively, and negatively charged guests, including seven fully or partially deuterated guests, have been determined in phosphate buffer solutions (pH/pD 6.9) of hydrogen oxide (H(2)O) or deuterium oxide (D(2)O) at 298.15 K by titration microcalorimetry. Upon complexation with these native and modified CDs, both nondeuterated and deuterated guests examined consistently exhibited higher affinities (by 5-20%) in D(2)O than in H(2)O. The quantitative affinity enhancement in D(2)O versus H(2)O directly correlates with the size and strength of the hydration shell around the charged/hydrophilic group of the guest. For that reason, negatively/positively charged guests, possessing a relatively large and strong hydration shell, afford smaller K(H2O)/K(D2O) ratios than those for neutral guests with a smaller and weaker hydration shell. Deuterated guests showed lower affinities (by 5-15%) than the relevant nondeuterated guests in both H(2)O and D(2)O, which is most likely ascribed to the lower ability of the C-D bond to produce induced dipoles and thus the reduced intracavity van der Waals interactions. The excellent enthalpy-entropy correlation obtained can be taken as evidence for the very limited conformational changes upon transfer of CD complexes from H(2)O to D(2)O.     

Structure,dynamics and thermodynamics of small particles and inorganic clusters

This invited review attempts to draw together recent advances in the structural characterisation of clusters and our theoretical understanding of dynamics, especially coexistence phenomena. It is now possible to characterise the potential energy surface of a small cluster in great detail, both in terms of local minima and transition states. A selection of results is collected includingab initio calculations on main group ligated clusters and a wide variety of systems bound by model analytic potentials. Useful comparisons may be made between the rearrangement mechanisms supported by the various potential energy surfaces. Furthermore, knowledge of transition states enables us to explain the results of dynamical simulations in great detail, and make comparisons with thermodynamic models. For larger systems, however, the number of stationary points is daunting, yet progress is still possible in terms of the underlying potential energy surface using the harmonic superposition approximation.     

Absolute free energies of binding of peptide analogs to the HIV-1 protease from molecular dynamics simulations

The constants of binding of five peptide analogs to the active site of the HIV-1 aspartic-protease are calculated based on a novel sampling scheme that is efficient and does not introduce any approximations in addition to the energy function used to describe the system. The results agree with experiments. The squared correlation coefficient of the calculated vs. the measured values is 0.79. The sampling scheme consists of a series of molecular dynamics integrations with biases. The biases are selected based on an estimate of the probability density function of the system in a way to explore the conformational space and to reduce the statistical error in the calculated binding constants. The molecular dynamics integrations are done with a vacuum potential using a short cutoff scheme. To estimate the probability density of the simulated system, the results of the molecular dynamics integrations are combined using an extension of the weighted histogram analysis method (C. Bartels, Chem. Phys. Letters 331 (2000) 446-454). The probability density of the solvated ligand-protein system is obtained by applying a correction for the use of the short cutoffs in the simulations and by taking into account solvation with an electrostatic term and a hydrophobic term. The electrostatic part of the solvation is determined by finite difference Poisson-Boltzmann calculations; the hydrophobic part of the solvation is set proportional to the solvent accessible surface area. Setting the hydrophobic surface tension parameter equal to 8 mol(-1) K(-1) A(-2), absolute binding constants are in the muM to nM range. This is in agreement with experiments. The standard errors determined from eight repeated binding constant determinations are a factor of 14 to 411. A single determination of a binding constant is done with 499700 steps of molecular dynamics integration and 4500 finite difference Poisson-Boltzmann calculations. The simulations can be analyzed with respect to conformational changes of the active site of the HIV-1 protease or the ligands upon binding and provide information that complements experiments and can be used in the drug development process.     

Direct calculation of the binding free energies of FKBP ligands

Direct calculations of the absolute free energies of binding for eight ligands to FKBP protein were performed using the Fujitsu BioServer massively parallel computer. Using the latest version of the general assisted model building with energy refinement (AMBER) force field for ligand model parameters and the Bennett acceptance ratio for computing free-energy differences, we obtained an excellent linear fit between the calculated and experimental binding free energies. The rms error from a linear fit is 0.4 kcal/mol for eight ligand complexes. In comparison with a previous study of the binding energies of these same eight ligand complexes, these results suggest that the use of improved model parameters can lead to more predictive binding estimates, and that these estimates can be obtained with significantly less computer time than previously thought. These findings make such direct methods more attractive for use in rational drug design.     

Polymer complexes. LXXII. Spectroscopic studies,thermodynamics, DNA binding and biological activity of polymer complexes

A novel series of copper polymer complexes ( 1 – 4 ) were synthesized and characterized using various spectroscopic techniques. Spectra of all polymer complexes a tetragonal distorted geometry for the Cu(II) ion. The electronic spectra, magnetic moments and electron spin resonance results indicate tetragonal distortion geometry for the Cu(II) polymer complexes. The effects of various solvents on absorption spectra of the ligand are discussed. A prediction of the interaction of the ligand against anti‐cancer receptors was carried out using AutoDock server. The affinity of the compounds to calf thymus DNA was determined through UV–visible DNA binding titration, and intrinsic binding constant (K_b) was found to be 4.16 × 10³, 3.10 × 10⁵, 3.18 × 10⁴ and 2.91 × 10⁵ for polymer complexes 1 – 4 , respectively. The antimicrobial activity of the polymer complexes against bacterial species (Bacillus cereus, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, Enterococcus faecalis and Pseudomonas aeruginosa) and fungal species (Aspergillus niger, Fusarium oxysporum and Candida albicans) was investigated.     

Electrochemistry of cytochrome C in aqueous and mixed solvent solutions: thermodynamics, kinetics, and the effect of solvent dielectric constant

The solvent dielectric constant is considered an important factor in determining the redox potential of the heme-containing protein cytochrome c in solution. In this study, we investigate the electrochemical response of cytochrome c in aqueous/organic solvent mixtures (100% aqueous buffer, 30% acetonitrile, 40% dimethyl sulfoxide, and 50% methanol), reporting the redox potential (E degrees'), enthalpy, and entropy of reduction. The temperature dependence of the solvent dielectric constant (epsilon) was also measured. The results show that epsilon alone cannot regulate the E degrees' of cytochrome c in mixed solvent systems. The implications of the temperature dependence of epsilon on the validity of the thermodynamic data are also discussed. The effect of solvent and temperature on the electron-transfer rate constant, k(s), was determined in each solvent mixture. A substantial increase in the activation energy for electron transfer was observed in 40% DMSO.     

Spectrophotometric study on the thermodynamics of binding of alpha- and beta-cyclodextrin towards some p-nitrobenzene derivatives

Binding properties of native alpha- and beta-cyclodextrin towards some nitrobenzene derivatives have been studied by means of UV-vis spectrophotometry. The former host is able to form complexes having 1:1 and 1:2 stoichiometric ratios with these guests, while only 1:1 complexes are detected with the latter host. A careful analysis of the thermodynamic parameters for complexation equilibria, under the perspective of the enthalpy-entropy compensation effect, reveals that binding abilities of the two different hosts are subject to different features.     

Rapid evaluation of the binding energies in hydrogen-bonded amide-thymine and amide-uracil dimers in gas phase

The binding energies and the equilibrium hydrogen bond distances as well as the potential energy curves of 48 hydrogen‐bonded amide–thymine and amide–uracil dimers are evaluated from the analytic potential energy function established in our lab recently. The calculation results show that the potential energy curves obtained from the analytic potential energy function are in good agreement with those obtained from MP2/6‐311+G** calculations by including the BSSE correction. For all the 48 dimers, the analytic potential energy function yields the binding energies of the MP2/6‐311+G** with BSSE correction within the error limits of 0.50 kcal/mol for 46 dimers, only two differences are larger than 0.50 kcal/mol and the largest one is only 0.60 kcal/mol. The analytic potential energy function produces the equilibrium hydrogen bond distances of the MP2/6‐311+G** with BSSE correction within the error limits of 0.050 Å for all the 48 dimers. The analytic potential energy function is further applied to four more complicated hydrogen‐bonded amide–base systems involving amino acid side chain and β‐sheet. The values of the binding energies and equilibrium hydrogen bond distances obtained from the analytic potential energy function are also in good agreement with those obtained from MP2 calculations with the BSSE correction. These results demonstrate that the analytic potential energy function can be used to evaluate the binding energies in hydrogen‐bonded amide–base dimers quickly and accurately. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011     

Molecular dynamics simulation, free energy calculation and structure-based 3D-QSAR studies of B-RAF kinase inhibitors

(V600E)B-RAF kinase is the most frequent onco-genic protein kinase mutation in melanoma and is a promising target to treat malignant melanoma. In this work, a molecular modeling study combining QM-polarized ligand docking, molecular dynamics, free energy calculation, and three-dimensional quantitative structure-activity relationships (3D-QSAR) was performed on a series of pyridoimidazolone compounds as the inhibitors of (V600E)B-RAF kinase to understand the binding mode between the inhibitors and (V600E)B-RAF kinase and the structural requirement for the inhibiting activity. 3D-QSAR models, including CoMFA and CoMSIA, were developed from the conformations obtained by QM-polarized ligand docking strategy. The obtained models have a good predictive ability in both internal and external validation. Furthermore, molecular dynamics simulation and free energy calculations were employed to determine the detailed binding process and to compare the binding mode of the inhibitors with different activities. The binding free energies calculated by MM/PBSA gave a good correlation with the experimental biological activity. The decomposition of free energies by MM/GBSA indicates the van der Waals interaction is the major driving force for the interaction between the inhibitors and (V600E)B-RAF kinase. The hydrogen bond interactions between the inhibitors with Glu501 and Asp594 of the (V600E)B-RAF kinase help to stabilize the DFG-out conformation. The results from this study can provide some insights into the development of novel potent (V600E)B-RAF kinase inhibitors.     

Molecular dynamics of hydrogen bonds in protein-D2O: the solvent isotope effect

We suggest that the H-bond in proteins not only mirrors the motion of hydrogen in its own atomistic setting but also finds its origin in the collective environment of the hydrogen bond in a global lattice of surrounding H2O molecules. This water lattice is being perturbed in its optimal entropic configuration by the motion of the H-bond. Furthermore, bonding interaction with the lattice drop the H-bond energy from some 5 kcal/mol for the pure protein in the absence of H2O, to some 1.6 kcal/mol in the presence of the H2O medium. This low value here is determined in a computer experiment involving MD calculations and is a value close to the generally accepted value for biological systems. In accordance with these computer experiments under ambient conditions, the H-bond energy is seriously depressed, hence confirming the subtle effect of the H2O medium directly interacting with the H-bond and permitting a strong fluxional behavior. Furthermore, water produces a very large change in the entropy of activation due to the hydrogen bond breakage, which affects the rate by as much as 2 orders of magnitude. We also observe that there is an entire ensemble of H-bond structures, rather than a single transition state, all of which contribute to this H-bond. Here the model is tested by changing to D2O as the surrounding medium resulting in a substantial solvent isotope effect. This demonstrates the important influence of the environment on the individual hydrogen bond.     

Structure of dimers of glycyrrhizic acid in water and their complexes with cholesterol: Molecular dynamics simulation

Journal of Structural Chemistry - The molecular dynamics simulation of dimers of glycyrrhizic acid (GA) arising from the spontaneous meeting of two GA molecules in water is performed. Shown that...     

Structure, dynamics, and thermodynamics of a family of potentials with tunable softness

We investigate numerically the structure, thermodynamics, and relaxation behavior of a family of (n, 6) Lennard-Jones-like glass-forming binary mixtures interacting via pair potentials with variable softness, fixed well depth, and fixed well depth location. These constraints give rise to progressively more negative attractive tails upon softening, for separations greater than the potential energy minimum. Over the range of conditions examined, we find only modest dependence of structure on softness. In contrast, decreasing the repulsive exponent from n=12 to n=7 causes the diffusivity to increase by as much as two orders of magnitude at fixed temperature and density, and produces mechanically stable packings (inherent structures) with cohesive energies that are, on average, ～1.7 well depths per particle larger than for the corresponding Lennard-Jones (n=12) case. The softer liquids have markedly higher entropies and lower Kauzmann temperatures than their Lennard-Jones (n=12) counterparts, and they remain diffusive down to appreciably lower temperatures. We find that softening leads to a modest increase in fragility.     

Collapse of diblock copolymer in poor solvent. Molecular dynamics study

The modification of unsaturated polyesters (UPE) by poly (ethylene glycol) (PEG) end groups [1] and the computer simulation of the collapse of a single molecule of a diblock copolymer AB consisting of PEG (A) and UPE (B) blocks [2] were reported recently by us. In the present paper the static and dynamic characteristics of the final collapsed structure were investigated by a molecular dynamics simulation. The structure and the local dynamic of collapsed homopolymers (AA and BB) were studied also. The initial conformations in all cases were taken near completely extended ones. The final structures of the diblocks are similar to the structure of a core (UPE) and shell (PEG) model. The differences in torsion angle distributions between diblock and homopolymer are maximal for the CCOC dihedral angles (both in UPE and PEG blocks). The orientational order of the COC vectors (‘chords’ along backbone of polymer chain) inside both blocks is larger in the diblock than in the homopolymer. Local orientational mobility of the COC vector and the translational mobility of the monomers is larger in the diblock than in the homopolymers for both blocks.