Conformational flexibility of a protein-carbohydrate complex and the structure and ordering of surrounding water

Protein-carbohydrate non-covalent interactions are important to understand various biological processes in living organisms. One of the important issues in protein-carbohydrate binding is how the protein identifies the target carbohydrate and recognizes its conformational features. Surrounding water molecules are expected to play a critical role not only in mediating the recognition process but also in maintaining the structure of the complex. We carried out atomistic molecular dynamics (MD) simulations of an aqueous solution of the protein-carbohydrate complex formed between the hyaluronan binding domain (HABD) of the murine Cd44 protein and the octasaccharide hyaluronan (HA(8)). The conformational flexibilities of the protein and the carbohydrate, and the microscopic structure and ordering of water molecules around them in the complexed form have been explored. It is revealed that the formation of the complex is associated with significant immobilization of the monosaccharide units of the carbohydrate moiety that are involved in binding. Further, reduction in water densities around the binding residues of the two molecules in the complex with respect to their free forms clearly demonstrated that the recognition between the protein and the carbohydrate is facilitated by removal of a fraction of water molecules from regions around the binding domains.     

Dynamic properties of water around a protein-DNA complex from molecular dynamics simulations

Formation of protein-DNA complex is an important step in regulation of genes in living organisms. One important issue in this problem is the role played by water in mediating the protein-DNA interactions. In this work, we have carried out atomistic molecular dynamics simulations to explore the heterogeneous dynamics of water molecules present in different regions around a complex formed between the DNA binding domain of human TRF1 protein and a telomeric DNA. It is demonstrated that such heterogeneous water motions around the complex are correlated with the relaxation time scales of hydrogen bonds formed by those water molecules with the protein and DNA. The calculations reveal the existence of a fraction of extraordinarily restricted water molecules forming a highly rigid thin layer in between the binding motifs of the protein and DNA. It is further proved that higher rigidity of water layers around the complex originates from more frequent reformations of broken water-water hydrogen bonds. Importantly, it is found that the formation of the complex affects the transverse and longitudinal degrees of freedom of surrounding water molecules in a nonuniform manner.     

Conformational transitions in macromolecules of complex chemical structure during liquid crystalline ordering

Conformational transitions in thermotropic main-chain polymers of complex chemical structure including homopolymers with possibility of conformational transformations in mesogens and random copolymers (CPLs) containing mesogens of the same type and spacers of different lengths were investigated. It was demonstrated that liquid crystalline (LC) state influences conformational transformations in fragments of chain restraining them in comparison with an isotropic melt. It was found that CPLs studied form LC order of smectic type. Peculiarities in spacers behaviour during transition to LC state ensure formation of such type of LC order. Conclusion about dependence of mechanism of smectic LC order formation on chemical structure of rigid components of CPLs is made.     

Spatial structure of water over the whole region of short-range ordering

A new approach to spatial analysis of molecular arrangement over the whole region of short-range ordering is suggested. The structural properties of water are calculated by the Monte-Carlo method using the SPC/E intermolecular interaction potential. Structural correlations are considered at distances of up to 10 Å. The functions g _OO, g _OH, and g _HH, and the partial functions corresponding to different local densities of surroundings and different coordination numbers of water molecules have been obtained. An analytical procedure has been developed to find the spatial distribution of particles, and the total and partial functions have been determined for particles of the same (having identical c.n.₁ and c.n.₂) and different types. The functions are considered for layers R _min < R < R _max corresponding to different coordination spheres of water molecules (up to 10 Å). A structural model of water is suggested, in which the deviation of the 3D net of H bonds from tetrahedricity is associated with the formation of configurations complementary to icelike configurations of water. The model is supported by the results of computer simulation.     

Conformational fluctuations and electronic properties in myoglobin

In this article we use the recently developed perturbed matrix method (PMM) to investigate the effect of conformational fluctuations on the electronic properties of heme in Myoglobin. This widely studied biomolecule has been chosen as a benchmark for evaluating the accuracy of PMM in a large and complex system. Using a long, 80-ns, molecular dynamics simulation and unperturbed Configuration Interaction (CISD) calculations in PMM, we reproduced the main spectroscopic features of deoxy-Myoglobin. Moreover, in line with our previous results on a photosensitive protein, this study reveals a clear dynamical coupling between electronic properties and conformational fluctuations, suggesting that this correlation could be a general feature of proteins.     

Restricted dynamics of water around a protein-carbohydrate complex: Computer simulation studies

Water-mediated protein-carbohydrate interaction is a complex phenomenon responsible for different biological processes in cellular environment. One of the unexplored but important issues in this area is the role played by water during the recognition process and also in controlling the microscopic properties of the complex. In this study, we have carried out atomistic molecular dynamics simulations of a protein-carbohydrate complex formed between the hyaluronan binding domain of the murine Cd44 protein and the octasaccharide hyaluronan in explicit water. Efforts have been made to explore the heterogeneous influence of the complex on the dynamic properties of water present in different regions around it. It is revealed from our analyses that the heterogeneous dynamics of water around the complex are coupled with differential time scales of formation and breaking of hydrogen bonds at the interface. Presence of a highly rigid thin layer of motionally restricted water molecules bridging the protein and the carbohydrate in the common region of the complex has been identified. Such water molecules are expected to play a crucial role in controlling properties of the complex. Importantly, it is demonstrated that the formation of the protein-carbohydrate complex affects the transverse and longitudinal degrees of freedom of the interfacial water molecules in a heterogeneous manner.     

Conformational ordering of chain molecules in liquid crystals

Deuterium NMR studies have been performed to elucidate orientational characteristics of some ether-type main-chain liquid crystals. Spacers used are of the type -O(CH₂)_nO- with n = 9 and 10. Dimers, homopolymers as well as copolymers in which spacers n = 9 and 10 are arranged in an alternative fashion were investigated. The quadrupolar splitting data obtained from the deuterium-labeled mesogenic core and spacer have been studied within the rotational isomeric state (RIS) approximation. The ordering characteristics thus estimated were found to be consistent with the magnetic susceptibility data obtained by using superconducting quantum interference device (SQUID) for the same polymers.     

Conformational ordering of apolar, chiral m-phenylene ethynylene oligomers

A series of m-phenylene ethynylene oligomers containing nonpolar, (S)-3,7-dimethyl-1-octanoxy side chains have been synthesized and studied. In apolar alkane solvents, oligomers of sufficient length (n > 10) were found to adopt a helical conformation with a large twist sense bias. In contrast, in chloroform the oligomers adopt a random coil conformation. Surprisingly, the strong twist sense bias was determined to be highly time dependent and is partially attributed to intermolecular aggregation.     

Differential flexibility of the secondary structures of lysozyme and the structure and ordering of surrounding water molecules

We have performed an atomistic molecular dynamics simulation of an aqueous solution of hen egg-white lysozyme at room temperature with explicit water molecules. Several analyses have been carried out to explore the differential flexibility of the secondary structural segments of the protein and the structure and ordering of water around them. It is found that the overall flexibility of the protein molecule is primarily controlled by few large-amplitude bistable motions exhibited by two coils; one connecting two α-helical segments in domain-1 and the other connecting a 3(10) helix and a β-sheet in domain-2 of the protein. The heterogeneous structuring of water around the segments of the protein has been found to depend on the degree of exposure of the segments to water. The ordering of water molecules around the protein segments and their tagged potential energies have been found to be anticorrelated with each other. Some of these findings can be verified by suitable experimental studies.     

Conformational flexibility in the peripheral site of Torpedo californica acetylcholinesterase revealed by the complex structure with a bifunctional inhibitor

The X-ray crystallographic structure of Torpedo californica acetylcholinesterase (TcAChE) in complex with the bifunctional inhibitor NF595, a potentially new anti-Alzheimer drug, has been solved. For the first time in TcAChE, a major conformational change in the peripheral-site tryptophan residue is observed upon complexation. The observed conformational flexibility highlights the dynamic nature of protein structures and is of importance for structure-based drug design.     

Raman study of the coordination structure of a rare Earth-acetate complex in water

The Raman spectra of aqueous LnCl(3) x 20H(2)O x CH3(C)OOLi (LnCl(3), rare earth chloride) solutions have been measured in the liquid state. The change of the Raman symmetric Ln(3+)-OH(2) stretching band (v(w)) showed that the decrease in the ionic radius of rare earth (Ln(3+)) ions induces a change in coordination number of the Ln(3+) ion. The two peaks at 946 and 958 cm(-1) of the C-C stretching band (v(CC)) of the acetate ion are assigned to the bidentate ligand and the polymeric chain structure, respectively. The coordination structure of the acetate ion to Ln(3+) ion prefers the bidentate ligand to the polymeric chain structure throughout the rare earth series. The fraction of the bidentate ligand increases with decreasing ionic radius of the Ln(3+) ion. On the basis of the analyses of the v(w) and v(CC) bands, the change in the coordination number of the Ln(3+) ion is mainly due to the structural change (from the polymeric chain structure to the bidentate ligand) of the Ln(3+)-acetate complex rather than a elimination of one water molecule. Our results show that the Ln(3+) ions tend to form the bidentate ligand rather than the divalent (M(2+)) ions.     

Conformational study of the trinucleotide CpGpCp-pentapeptide Gly5 complex: The important role of bridging water in the complex formation

Conformational changes in the RNA-protein interaction were studied by calculating the intramolecular interaction energy of a model complex with the use of potential functions. The model complex has hydrogen-bonded water molecules bridging polypeptide NH groups to 2'-hydroxyl groups and sugar ring oxygen atoms. Since the sugar ring is constrained by the bridging water, preliminary calculations with the model compounds, the sugar ring, mononucleoside diphosphates, pCp and pGp, were carried out, and the flexibility and energetics of the sugar ring were compared with the previous results of DNA. The shift of the phase angle of the sugar ring occurred in the complex formation because of the hydrogen bond through the bridging water and the flexibility of the sugar ring. The free energy difference at 298 K is about ?74.0 kcal/mol which was obtained from the intramolecular interaction energy difference of ?67.5 kcal/mol by adding the conformational entropy change of 21.9 e.u., which in turn was calculated from the evaluation of the determinant of the matrix containing variances and covariances of the internal coordinates.     

Conformational structure of divinylacetylene

Ab initio quantum chemical calculations of the divinylacetylene molecule with different mutual orientations of vinyl groups are carried out using the 6–31G*/MP2 basis set. The torsional potential is approximated by a Fourier series. It is shown that the second term of the series dominates. The enthalpies of the cis- and trans-isomers are nearly equal; the maximum corresponds to the gosh-orientation (180.4 cm⁻¹ with respect to the cis-form). The vibrational spectra of the compounds with cis-, gosh-, and trans-orientations of vinyl groups are analyzed based on the ab initio calculations. It is concluded that the experimental data available in the literature agree with the hypothesis that divinylacetylene exists as cis- and trans-isomers. Translated fromZhumal Strukturnoi Khimii, Vol. 39, No. 4, pp. 610–617, July–August, 1998.     

The natural DNA bending angle in the lac repressor headpiece-O1 operator complex is determined by protein-DNA contacts and water release

We performed molecular dynamics simulations of the lac repressor headpiece-O1 operator complex for natural, over and underbent DNA to assess the factors that determine the natural DNA bending angle. At the natural angle, the specific and nonspecific contacts between the protein and DNA are optimized. Protein-DNA contacts show different angle dependences in the right and left sites, with the left site generally getting weaker and the right site getting stronger as the bending angle increases. Two entropic factors were identified as well: at the natural bending angle, water release and the quasiharmonic protein configurational entropy are maximized. The gain in protein configurational entropy might stem from an entropy-entropy compensation mechanism, in which a reduction in protein fluctuations is offset by a loss in correlations between the right and left sites.     

The water structure around the chloride ion in aqueous polyethylene oxide solutions

Neutron diffraction and nuclear magnetic relaxation yield complementary information on the interaction of ions and water molecules in solution. In the present study the two techniques are used to investigate the influence of poly (ethyleneoxide) on the Cl⁻ hydration sphere. It is concluded that the important effect of PEO on the ³⁵Cl relaxation rate is due to the occurrence of a long correlation time rather than structural changes.     

Conformational energetics and excited state level ordering in 11-cis retinal.

Semiempirical molecular orbital theory and semiclassical solvent effect theory are used to analyze the conformational and electronic properties of the 12-s-cis and 12-s-trans conformers of 11-cis retinal. The goal is to examine the influence of solvent environment on the equilibrium geometries of these conformers as well as to provide a perspective on the electronic transitions that contribute to the four band systems that are observed in the 200-500 nm region of the optical spectrum. We conclude that the 12-s-cis isomer is more stable in vacuum, but that the 12-s-trans conformer is preferentially stabilized in both polar and nonpolar solvent environment due to dispersive as well as electrostatic interactions. This observation is in substantial agreement with previous literature results. In contrast, our analysis of the excited state manifold indicates that the spectral features observed in the absorption spectrum are associated with a complex set of overlapping transitions. A total of 18 pi*<--pi transitions contribute to the four bands, and in some cases, conformation changes the relative contribution of the individual transitions that define the overall band shape. This study provides the first definitive assignments for all four band systems.     

Conformational study of glycyl-L-proline technetium complex

Quantitative measurement of fission and activation products resulting from neutron irradiation of fissile materials is of interest for applications in environmental monitoring, nuclear waste management, and national security. Based on established separation processes involving co-precipitation, solvent extraction, and ion-exchange and extraction chromatography, we have optimized a proposed sequence of separation steps to allow for the timely quantification of analytes of interest. We have recently evaluated this scheme using an irradiated sample to examine the adequacy of separations for measurement of desired analytes by gamma spectrometry. Here we present the radiochemical separations utilized and the yields and purity obtained.     

Conformational changes of a polyelectrolyte in mixtures of water and acetone

Samples of a polyelectrolyte poly(methacryloylethyl trimethylammonium methylsulfate), PMETMMS, with molar masses M_w = 22−25 × 10⁶ were examined with viscosity, static light scattering, and conductivity measurements in a water–acetone solvent. Because acetone is a nonsolvent for this polymer the measurements were performed to determine the influence of the solvent composition, the polymer concentration, and the presence of added ions on the conformation of the polyelectrolyte in mixed solvents. The possible influence of a hydrodynamic field on the polymer conformation was also studied. The viscosity of the polymer solutions as a function of polymer concentration, as well as of the solvent composition, was studied using a broad range of shear rates. When the mass fraction of acetone in the solvent, γ, is below 0.5, the solutions show a usual polyelectrolyte behavior. When γ ≥ 0.80, the polymer adopts a compact conformation. This is observed as a decrease of the radius of gyration, R_g, second virial coefficient, A₂, the viscosity, and also as a change in the conductivity of the solution. The change in the polymer conformation may be induced also by dilution. When 0.60 ≤ γ < 0.80, a gradual decrease in the polymer concentration leads to a sudden decrease of the reduced viscosity, which indicates a decrease in the particle size. The values of M_w measured by static light scattering were constant in all experiments. © 1998 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 36: 1107–1114, 1998