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PubMed2006

Base triplet nonisomorphism strongly influences DNA triplex conformation: effect of nonisomorphic G* GC and A* AT triplets and bending of DNA triplexes.

Structural understanding of DNA triplexes is grossly inadequate despite their efficacy as therapeutic agents. Lack of structural similarity (isomorphism) of base triplets that figure in different DNA triplexes brings in an added complexity. Recently, we have shown that the residual twist (Deltat degrees ) and the radial difference (Deltar A) adequately define base triplet nonisomorphism in structural terms and allow assessment of their role in conferring stability as well as sequence-dependent structural variations in DNA triplexes. To further corroborate these, molecular dynamics (MD) simulations are carried out on DNA triplexes comprising nonisomorphic G* GC and A* AT base triplets under different sequential contexts. Base triplet nonisomorphism between G* GC and A* AT triplets is dominated by Deltat degrees (9.8 degrees ), in view of small Deltar (0.2 A), and is in contrast to G* GC and T* AT triplets where both Deltat degrees (10.6 degrees ) and Deltar (1.1A) are prominent. Results show that Deltat degrees alone enforces mechanistic influence on the triplex-forming purine strand so as to favor a zigzag conformation with alternating conformational features that include high (40 degrees ) and low (20 degrees ) helical twists, and high anti(G) and anti(A) glycosyl conformation. Higher thermal stability of this triplex compared to that formed with G* GC and T* AT triplets can be traced to enhanced base-stacking and counterion interactions. Surprisingly, it is found for the first time that the presence of a nonisomorphic G* GC or A* AT base triplet interrupting an otherwise mini A* AT or G* GC isomorphic triplex can induce a bend/curvature in a DNA triplex. These observations should prove useful in the design of triplex-forming oligonucleotides and in the understanding the binding affinities of this triplex with proteins.

Adenine↗
PubMedDate not supplied

DNA bending induced by carbocyclic sugar analogs constrained to the north conformation.

DNA bending caused by introduction of carbocyclic sugars constrained to the north conformation was studied, using explicit solvent molecular dynamic (MD) simulations. The native Drew-Dickerson (DD) dodecamer and its three modifications containing north carbocyclic sugars in the 7th (T7*), 8th (T8*) or both 7th and 8th (T7T8*) nucleotide positions were examined. Introduction of the carbocyclic sugar results in A-form conformations for the alpha, beta, chi, zeta, and sugar pucker backbone parameters in the modified nucleotides. Increased steric repulsion between the sugar and its parent base in the modified oligonucleotides impacts the roll and cup dinucleotide step parameters, increasing the bending of the oligomer axis. Increased buckling of the substituted nucleotides disrupts the usual stabilizing base stacking interactions. The level of overall bending depends on the number and position of carbocyclic sugars introduced in the DNA sequence. Single sugar substitutions are unable to induce substantial bending due to the neighboring unmodified nucleotides counterbalancing the distortion. Significant bending can, however, be induced by two consecutive north sugars (T7T8*), which is in agreement with experimental results. The modified oligomers populate a wide range of bend angles, indicating that they maintain flexibility in the bent state. The present results suggest that insertion of carbocyclic sugars into DNA or RNA duplexes can be used to engineer bending of the duplexes without impacting the electrostatic or chemical properties of the phosphodiester backbone, thereby serving as excellent tools for experimental elucidation of nucleic acid structure-function relationships.

Base Pairing↗
PubMed2005

Musings on ADME predictions and structure-activity relations.

The first part of the paper examines Structure-Activity Relations (SARs) and their components from a very general point of view. The various types of interpretation emerging from statistically valid relations will be examined, namely causal (mechanistic), contextual (empirical), fortuitous, and tautological correlations. Implications for ADME predictions will be seen when discussing the diversity of interactions between active compounds (e.g., drugs) and biological systems. The second part of the paper is more specific and presents the concept of molecular-property space, an all but neglected concept in SARs. Recent results from Molecular Dynamics (MD) simulations and Molecular Interaction Fields (MIF) computations of acetylcholine will be used to illustrate not only the well-known conformational space of this molecule, but also its property space as exemplified by its lipophilicity space. It will be seen that a molecule as small as acetylcholine is able to span a relatively broad property space. Most significantly in an ADME perspective, the molecule is able, within the limits of its property space, to adapt to the medium. This is equivalent to saying that the medium constrains the molecule to resemble it as much as feasible.

Forecasting↗
PubMed2006

Ternary nickel(II) complexes as hydrolytic DNA-cleavage agents.

A series of small model complexes made from Ni(II) and the ligands ethylenediamine (en), histamine (hist), and histidylleucine (HisLeu) were prepared and studied as potential hydrolytic DNA-cleavage agents. The stability constants and species-distribution curves for these complexes were determined as a function of pH. The 1 : 1 : 1 ternary complexes [Ni(II)(en)(HisLeu)] (1) and [Ni(II)(hist)(HisLeu)] (2) were the only major species present at the physiologically relevant pH of 6-7, as further corroborated by ESI-MS analysis. The complex geometries of 1 and 2 were analyzed by UV/VIS experiments and molecular dynamics (MD) simulations. Both ternary complexes were found to intercalate with DNA, as shown by UV/VIS, thermal-denaturation, and fluorescence-titration studies with ethidium bromide (EB). The intrinsic binding constants (K(b)) for the bound complexes 1DNA and 2DNA were determined as 150 and 290, resp. Gel-electrophoresis experiments revealed that 1 and 2 cleave supercoiled (type-I) to nicked-circular (type-II) DNA at physiological pH, with rate constants of 0.64 and 0.75 h(-1), resp. A tentative mechanism for this hydrolytic cleavage is proposed.

DNA Cleavage↗
PubMed2006

Conformational fluctuations versus constraints in amino acid side chains: the evolution of information content from free amino acids to proteins.

Like all other complex biological systems, proteins exhibit properties not found in free amino acids (i.e., emergent properties). Here, we explore top-down constraints experienced by the residue side chains in proteins compared to amino acids in increasingly complex molecular environments: free amino acids, end-capped amino acids, and the central residue in an alpha-helical nonapeptide. The crystalline structure of the contractile protein profilin Ib and the enzyme trypsin were chosen as objects of study, and submitted to 10 ns molecular dynamics (MD) simulations. The results revealed increased conformational constraints on the side chains when going from the simpler to the more complex compounds. A Shannon entropy (SE) analysis of the conformational behavior of the side chains showed in most cases a progressive and marked decrease in the SE of the chi1 and chi2 dihedral angles. This is equivalent to stating that conformational constraints on the side chain of residues increase their information content and, hence, recognition specificity compared to free amino acids. In other words, the vastly increased information content of a protein relative to its free monomers is embedded not only in the tertiary structure of the backbone, but also in the conformational behavior of the side chains. The postulated implication is that both backbone and side chains, by virtue of being conformationally constrained, contribute to the protein's recognition specificity toward other macromolecules and ligands.

Amino Acids↗
PubMed2005

Molecular basis of the interaction specificity between the human glucocorticoid receptor and its endogenous steroid ligand cortisol.

We analyzed the binding of five steroids to the human glucocorticoid receptor (hGR) experimentally as well as theoretically. In vitro, we measured the binding affinity of aldosterone, cortisol, estradiol, progesterone, and testosterone to hGR in competition with the ligand dexamethasone. The binding affinity relative to the endogenous ligand cortisol (100%) is reduced for progesterone (22%) and aldosterone (20%) and is very weak for testosterone (1.5%) and estradiol (0.2%). In parallel, we constructed a homology model of the hGR ligand-binding domain (LBD) based on the crystal structure of the human progesterone receptor (hPR). After docking the five steroids into the hGR model ligand-binding pocket, we performed five separate 4-ns molecular dynamics (MD) simulations with these complexes in order to study the complex structures. We calculated the binding affinities with two different approaches (MM/PBSA, FlexX) and compared them with the values of the experimentally determined relative binding affinities. Both theoretical methods allowed discrimination between strongly and weakly binding ligands and recognition of cortisol as the endogenous ligand of the hGR in silico. Cortisol binds most strongly due to a nearly perfect steric and electrostatic complementarity with the hGR binding pocket. Chemically similar ligands such as estradiol, testosterone, and progesterone also fit into the hGR binding pocket, but they are unable to form all those contacts with the amino acids of the protein that are necessary to yield a stable, transcriptionally active receptor conformation. Our analysis thus explains the selectivity of the human glucocorticoid receptor for its endogenous ligand cortisol at a molecular level.

Amino Acids↗
PubMed2003

Electrostatic complexation and photoinduced electron transfer between Zn-cytochrome c and [olyanionic fullerene dendrimers.

Two dendritic fullerene (DF) monoadducts, 2 and 3, which can carry up to 9 and 18 negative charges, respectively, were examined with respect to electrostatic complexation with Cytochrome c (Cytc). To facilitate comprehensive photophysical investigations, the zinc analogue of Cytc (ZnCytc) was prepared according to a novel, modified procedure. The association of ZnCytc and DF, and consequential photoinduced electron transfer within ZnCytc-DF from the photoexcited protein to the fullerene, was proven by fluorescence spectroscopy and transient absorption spectroscopy. These findings were also supported by circular dichroism as well as by extensive molecular dynamics (MD) simulations.

Anions↗
PubMed2003

Molecular switch triggered by solvent polarity: synthesis, Acid-base behavior, alkali metal ion complexation, and crystal structure.

The synthesis and characterization of the new tetraazamacrocycle L, bearing two 1,1'-bis(2-phenol) groups as side-arms, is reported. The basicity behavior and the binding properties of L toward alkali metal ions were determined by means of potentiometric measurements in ethanol/water 50:50 (v/v) solution (298.1+/-0.1 K, I=0.15 mol dm(-3)). The anionic H(-1)L(-) species can be obtained in strong alkaline solution, indicating that not all of the acidic protons of L can be removed under the experimental conditions used. This species behaves as a tetraprotic base (log K(1)=11.22, log K(2)=9.45, log K(3)=7.07, log K(4)=5.08), and binds alkali metal ions to form neutral [MH(-1)L] complexes with the following stability constants: log K(Li)=3.92, log K(Na)=3.54, log K(K)=3.29, log K(Cs)=3.53. The arrangement of the acidic protons in the H(-1)L(-) species depends on the polarity of the solvents used, and at least one proton switches from the amine moiety to the aromatic part upon decreasing the polarity of the solvent. In this way two different binding areas, modulated by the polarity of solvents, are possible in L. One area is preferred by alkali metal ions in polar solvents, the second one is preferred in solvents with low polarity. Thus, the metal ion can switch from one location to the other in the ligand, modulated by the polarity of the environment. A strong hydrogen-bonding network should preorganize the ligand for coordination, as confirmed by MD simulations. The crystal structure of the [Na(H(-1)L)].CH(3)CN complex (space group P2(1)/c, a=12.805(1), b=20.205(3), c=14.170(2) A, beta=100.77(1) degrees, V=3601.6(8) A(3), Z=4, R=0.0430, wR2=0.1181), obtained using CH(2)Cl(2)/CH(3)CN as mixed solvent, supports this last aspect and shows one of the proposed binding areas.

Journal Article↗
PubMed2005

An NMR and molecular modeling study of carbosilane-based dendrimers functionalized with phenolic groups or titanium complexes at the periphery.

Dendrimers are modified polymers whose architecture is defined by the presence of a central atom or core with multiple branches. These molecules lend themselves to a variety of architectures and uses, including drug delivery and catalysis. The study of the molecular conformations and shapes of dendritic molecules is necessary but not yet routine. Here we present an NMR and molecular modeling study of a series of carbosilane dendrimers, namely 1G-{(CH2)3[C6H3(OMe)]OH}4 (1), 2G-{(CH2)3[C6H3(OMe)]OH}8 (2), and 2G-{(CH2)3[C6H3(OMe)]O[Ti(C5H5)Cl2]}8 (3). Various two-dimensional NMR techniques were used to completely assign the 1H and 13C resonances of molecules 1-3. This information was used, in conjunction with 1H and 13C spin-lattice relaxation measurements, to assess the chain motion of the molecules. The NMR data were also compared with 1-ns molecular dynamics (MD) simulations of 1 and 2 using the MMFF94 force field. The results indicate that these dendrimers possess a core that is motionally decoupled from the rest of the dendrimer, with flexible arm segments that extend from the core. The addition of eight functionalized titanium groups to the ends of the dendrimer chains of 2 to yield molecule 3 serves to further restrict chain motion.

Journal Article↗
PubMed2004

Local dense structural heterogeneities in liquid water from ambient to 300 MPa pressure: evidence for multiple liquid-liquid transitions.

Difference and double-difference near-infrared DO-D and HO-H stretching overtone (2nuOD and 2nuOH) spectroscopy and a rigorous (physically substantiated) band deconvolution technique were applied to reveal three different kinds of inherent (interstitial) structures of liquid water, which determine its high density (compared to ice lh under ambient conditions), its compressibility (under hydrostatic pressure, up to 300MPa), and its high fragility (manifested under temperature variation). Our data processing allowed the rigorous discrimination of up to six vibrational components. On the basis of an extensive comparative analysis combined with available structural data (X-ray and neutron scattering) and molecular dynamics (MD) simulations for liquid water, as well as with experimental and computed data for small non-tetrahedrally arranged water clusters, the major four components could be ascribed to: i) The basic lh icelike substructure; ii) the temperature-dependent remote interstitial "defects" due to tetrahedral displacements (primarily responsible for transport properties); iii) the interstitial "defects" most probably arranged in quasiplanar noncyclic tetramers (totally absent in the ice structure); and iv) the interstitial "defects" formed with increasing pressure, probably arranged in cubic water octamers and composed of two pairs of noncyclic and cyclic tetramer fragments. The latter structures include, essentially, bent hydrogen bonds stabilized by resonance effects.

Journal Article↗
PubMed2006

Optical properties of gas-phase tryptophan-silver cations: charge transfer from the indole ring to the silver atom.

We present a joint experimental and theoretical investigation of the electronic excitation spectra of the tryptophan-silver complex. The photodissociation spectrum of gas-phase [Trp-Ag]+ was measured from 215 to 330 nm using a quadrupole ion trap coupled to an optical parametric-oscillator laser. The calculated time-dependent density functional theory (TD-DFT) absorption spectra for different prototypes of structures are presented. Low-energy transitions that are experimentally observed are only calculated for the charge-solvation (CS) structures. These transitions are a signature of the metal-pi interaction in [Trp-Ag]+. The recorded spectrum is compared to a Boltzmann average of the absorption spectrum obtained from direct molecular dynamics (MD) simulations involving simultaneous transitions to excited states based on semiempirical configuration interaction (CI) calculations. The results demonstrate that charge transfer can be photoinduced from the indole ring to the silver atom.

Cations, Monovalent↗
PubMed2006

Alternative low-energy mechanisms for isotopic exchange in gas-phase D2O-H+(H2O)n reactions.

Molecular-dynamics (MD) trajectories and high-level ab initio methods have been used to study the low-energy mechanism for D(2)O-H(+)(H(2)O)(n) reactions. At low collisional energies, MD simulations show that the collisional complexes are long-lived and undergo fast monomolecular isomerization, converting between different isomers within 50-500 ps. Such processes, primarily involving water-molecule shifts along a water chain, require the surmounting of very-low-energy barriers and present sizable non- Rice-Ramsperger-Kassel-Marcus (RRKM) effects, which are interpreted as a lack of randomization of the internal kinetic energy. Interestingly, the rate of water shifts was found to increase upon increasing the size of the cluster. Based on these findings, we propose to incorporate the following steps into the mechanism for low-energy isotopic scrambling these D(2)O-H(+)(H(2)O)(n) reactions: a) formation of the collisional complex [H(+)(H(2)O)(n)D(2)O]* in a vibro-rotational excited state; b) incorporation of the heavy-water molecule in the cluster core as HD(2)O(+) by means of isomerization involving molecular shifts; c) displacement of solvation molecules from the first shell of HD(2)O(+) inducing de-deuteration (shift of a D(+) to a neighbor water molecule); d) reorganization of the clusters and/or expulsion of one of the isotopic variants of water (H(2)O, HDO or D(2)O) from the periphery of the complex.

Journal Article↗
PubMed2003

Structural and dynamical properties of methane clathrate hydrates.

Equilibrium molecular dynamics (MD) simulations have been performed in both the NVT and NPT ensembles to study the structural and dynamical properties of fully occupied methane clathrate hydrates at 50, 125, and 200 K. Five atomistic potential models were used for water, ranging from fully flexible to rigid polarizable and nonpolarizable. A flexible and a rigid model were utilized for methane. The phonon densities of states were evaluated and the localized rattling modes for the methane molecules were found to couple to the acoustic phonons of the host lattice. The calculated methane density of states was found to be in reasonable agreement with available experimental data.

Journal Article↗
PubMed2005

Structure-breaking effects of solvated Rb(I) in dilute aqueous solution--an ab initio QM/MM MD approach.

Structural properties of the hydrated Rb(I) ion have been investigated by ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations at the double-zeta HF quantum mechanical level. The first shell coordination number was found to be 7.1, and several other structural parameters such as angular distribution functions, radial distribution functions and tilt- and theta-angle distributions allowed the full characterization of the hydration structure of the Rb(I) ion in dilute aqueous solution. Velocity autocorrelation functions were used to calculate librational and vibrational motions, ion-ligand motions, as well as reorientation times. Different dynamical parameters such as water reorientation, mean ligand residence time, the number of ligand exchange processes, and rate constants were also analyzed. The mean ligand residence time for the first shell was determined as tau = 2.0 ps.

Journal Article↗
PubMed2005

Application of torsion angle molecular dynamics for efficient sampling of protein conformations.

We investigate the application of torsion angle molecular dynamics (TAMD) to augment conformational sampling of peptides and proteins. Interesting conformational changes in proteins mainly involve torsional degrees of freedom. Carrying out molecular dynamics in torsion space does not only explicitly sample the most relevant degrees of freedom, but also allows larger integration time steps with elimination of the bond and angle degrees of freedom. However, the covalent geometry needs to be fixed during internal coordinate dynamics, which can introduce severe distortions to the underlying potential surface in the extensively parameterized modern Cartesian-based protein force fields. A "projection" approach (Katritch et al. J Comput Chem 2003, 24, 254-265) is extended to construct an accurate internal coordinate force field (ICFF) from a source Cartesian force field. Torsion crossterm corrections constructed from local molecular fragments, together with softened van der Waals and electrostatic interactions, are used to recover the potential surface and incorporate implicit bond and angle flexibility. MD simulations of dipeptide models demonstrate that full flexibility in both the backbone phi/psi and side chain chi1 angles are virtually restored. The efficacy of TAMD in enhancing conformational sampling is then further examined by folding simulations of small peptides and refinement experiments of protein NMR structures. The results show that an increase of several fold in conformational sampling efficiency can be reliably achieved. The current study also reveals some complicated intrinsic properties of internal coordinate dynamics, beyond energy conservation, that can limit the maximum size of the integration time step and thus the achievable gain in sampling efficiency.

Computer Simulation↗
PubMed2006

Ab initio QM/MM dynamics of H3O+ in water.

A molecular dynamics (MD) simulation based on a combined ab initio quantum mechanics/molecular mechanics (QM/MM) method has been performed to investigate the solvation structure and dynamics of H3O+ in water. The QM region is a sphere around the central H3O+ ion, and contains about 6-8 water molecules. It is treated at the Hartree-Fock (HF) level, while the rest of the system is described by means of classical pair potentials. The Eigen complex (H9O4+) is found to be the most prevalent species in the aqueous solution, partly due to the selection scheme of the center of the QM region. The QM/MM results show that the Eigen complex frequently converts back and forth into the Zundel (H5O2+) structure. Besides the three nearest-neighbor water molecules directly hydrogen-bonded to H3O+, other neighbor waters, such as a fourth water molecule which interacts preferentially with the oxygen atom of the hydronium ion, are found occasionally near the ion. Analyses of the water exchange processes and the mean residence times of water molecules in the ion's hydration shell indicate that such next-nearest neighbor water molecules participate in the rearrangement of the hydrogen bond network during fluctuative formation of the Zundel ion and, thus, contribute to the Grotthuss transport of the proton.

Computer Simulation↗
PubMed2005

Physicochemical and structural characterization of quercetin-beta-cyclodextrin complexes.

Quercetin is a bioactive flavonoid widely used as a health supplement. Being sparingly soluble and chemically unstable in aqueous intestinal fluids, quercetin is poorly absorbed orally. This study aimed to investigate the effects of three beta-cyclodextrins, namely, unsubstituted beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and sulfobutyl ether beta-cyclodextrin (SBE-beta-CD) on the chemical stability and water solubility of quercetin, and to elucidate the complexation mechanisms of these beta-CDs with quercetin. Quercetin-beta-CD complexes in solution were characterized by stability assessment, phase solubility measurements, and 1H-nuclear magnetic resonance (NMR) spectroscopy. Molecular modeling was used to help establish the mode of interaction of the beta-CDs with quercetin. Solubility enhancements of quercetin obtained with the three beta-CDs followed the rank order: SBE-beta-CD > HP-beta-CD > beta-CD. The stability of quercetin at alkaline pHs also showed substantial improvement. NMR spectroscopic analysis suggested that the B-ring, C-ring, and part of the A-ring of quercetin display favorable interaction with the hydrophobic cavity of the beta-CDs, which was confirmed by molecular dynamics (MD) simulations using a solvated model of the quercetin-beta-CD complex. An inclusion complex model has been established for explaining the observed augmentation of solubility and stability of quercetin in water by beta-CDs.

Chemical Phenomena↗
PubMed2006

Conformational structure, dynamics, and solvation energies of small alanine peptides in water and carbon tetrachloride.

The rate-limiting barrier for peptide transport across lipid bilayers is the nonpolar hydrocarbon interior. Permeating peptides may undergo conformational changes during their transfer from an aqueous solution into the barrier domain, thus facilitating peptide transport. To test this hypothesis, all-atom and explicit-solvent molecular dynamics (MD) simulations have been conducted on a series of small peptides, p-toluyl-Ala(n) (n = 0-3) used previously in transport experiments, to explore their conformational structures, dynamics and solvation free energies in water and carbon tetrachloride (CCl(4)). The conformations of the p-toluyl alanine di- and tri-peptides in water were found to be far from random coils, with P(II) and alpha(R) dominating but with smaller populations of seven-membered (c(7)) and five-membered rings (c(5)). In contrast, the seven-membered ring, c(7), along with c(5) dominated in CCl(4). These results indicate that the conformational preferences of the alanine peptides are highly sensitive to solvent. Dynamically, stable seven-membered ring formation occurred on a time scale of 10 ps while larger ring-sizes (e.g., 10-membered rings) were observed much less frequently. The values of adjacent torsional angles (phi(1), psi(1)) were dependent on neighboring torsional angles. Thermal motions of neighboring torsions leading to transitions between c(7), c(5), alpha(R), and P(II) conformers were highly cooperative while longer range correlations between transitions of adjacent sets of torsions (phi(1), psi(1)) and (phi(2), psi(2)) were less evident. Peptide folding in CCl(4) lowers the intramolecular electrostatic energies. This, along with hydrophobic interactions, favors partitioning into CCl(4). These effects only partially offset other types of intramolecular interactions and peptide-solvent polar interactions that are more favorable in water, leading to net transfer free energies (3-7 kcal/mol) that disfavor peptide transfer from water into carbon tetrachloride.

Alanine↗