Changes In Molecular Properties Research Articles

Hierarchical Analysis of Bioactive Matched Molecular Pairs, Encoded Chemical Transformations, and Associated Substructures

The matched molecular pair (MMP) concept has become popular to assess molecular property changes resulting from small chemical modifications and study structure-activity relationships (SARs). In this study, we further extend MMP analysis by introducing an MMP-based hierarchical analysis scheme. Specifically, we report a large-scale analysis of MMPs derived from bioactive compounds following a defined "MMP-transformation-substructure" hierarchy. This makes it also possible to categorize transformations and corresponding substructures on the basis of activity information. MMPs were systematically generated for compounds active against current pharmaceutical targets and stepwise decomposed into transformations and substructures. Surprisingly, most chemical transformations were only associated with single MMPs. Hence, the structural context of transformations was unexpectedly narrow. In addition, nearly half of all substructures were found to exclusively form single-target transformations. Taken together, the results of our analysis provide a detailed view of MMP-transformation-substructure hierarchy and further increase the knowledge base of the MMP approach.

Electric properties of the low-lying excited states of benzonitrile: geometry relaxation and solvent effects

Accurate calculations of the dipole moment and the polarizability for the ground and two lowest singlet and triplet excited states of benzonitrile (BN) have been performed by a variety of wave function and density functional theory (DFT) methods. Changes in molecular properties upon the electron excitation strongly depend on the character of an excited state. The vertical dipole moment change and the excess polarizability for the 11B state are smaller than those for the 21A state. In order to estimate adiabatic excited-state properties, corresponding relaxed geometries have been obtained using the PBE0 functional with the aug-cc-pVTZ basis set. The excited-state property values obtained with the long-range exchange corrected DFT methods are in general closer to the coupled cluster (CC) results, although the hybrid DFTs also provide reasonable predictions. Our CCSD adiabatic excess dipole moment value for the 11B state equal to 0.11 D is in excellent agreement with the experimental value. The 21A state appears to be more sensitive to selected method due to an important role of double-excitation effects. Solvent effects on dipole moment and polarizability of BN molecule in its ground and excited states were evaluated using both LR and cLR methods combined with the (TD-)CAMB3LYP/POL approach.

Phase-transition properties of glycerol–dipalmitate lipid bilayers investigated using molecular dynamics simulation

The phase- and phase-transition properties of glycerol–dipalmitate (GDP) bilayer patches are investigated using molecular dynamics simulations. This permits to characterize the influence of introducing a second aliphatic lipid tail by comparison to previously reported simulations of glycerol-1-monopalmitate (GMP). To this purpose, a set of 67 simulations (up to 300ns duration) of 2×8×8GDP bilayer patches are performed, considering the two GDP isomers glycerol-1,3-dipalmitate (13GDP) and glycerol-1,2-dipalmitate (12GDP; racemic), two hydration levels (12GDP only), and temperatures in the range 250–370K. In agreement with experiment, the GDP simulations reveal an increase in the main transition temperature by about 25K relative to GMP, and the occurrence of non-bilayer phases at high temperatures (inverted-cylinder or stacked phases). Structurally, the GDP system tends to evidence a tighter packing of the chains, a reduced extent of tilting, increased order parameters and a reduced fluidity. These differences are easily interpreted in terms of two key changes in molecular properties when going from GMP to GDP: (i) the reduction of the headgroup polarity and hydration (from two free hydroxyl groups to a single one); (ii) the increase in the effective tail cross-section relative to the (hydrated) headgroup cross-section, conferring to GDP a particular wedge shape. These two effects contribute to the relative instability of the liquid-crystalline phase, the stability being recovered in nature when the diglyceride headgroup is functionalized by a bulky or/and polar substituent.

The influence of spacer units on molecular properties and solar cell performance of non-fullerene acceptors

The position of methyl groups causes a dramatic change in molecular properties and solar cell performance.

A High-Throughput Cell-Based Method to Predict the Unbound Drug Fraction in the Brain

Optimization of drug efficacy in the brain requires understanding of the local exposure to unbound drug at the site of action. This relies on measurements of the unbound drug fraction (fu,brain), which currently requires access to brain tissue. Here, we present a novel methodology using homogenates of cultured cells for rapid estimation of fu,brain. In our setup, drug binding to human embryonic kidney cell (HEK293) homogenate was measured in a small-scale dialysis apparatus. To increase throughput, we combined drugs into cassettes for simultaneous measurement of multiple compounds. Our method estimated fu,brain with an average error of 1.9-fold. We propose that our simple method can be used as an inexpensive, easily available and high-throughput alternative to brain tissues excised from laboratory animals. Thereby, estimates of unbound drug exposure can now be implemented at a much earlier stage of the drug discovery process, when molecular property changes are easier to make.

MicroScale Thermophoresis: Interaction analysis and beyond

MicroScale Thermophoresis (MST) is a powerful technique to quantify biomolecular interactions. It is based on thermophoresis, the directed movement of molecules in a temperature gradient, which strongly depends on a variety of molecular properties such as size, charge, hydration shell or conformation. Thus, this technique is highly sensitive to virtually any change in molecular properties, allowing for a precise quantification of molecular events independent of the size or nature of the investigated specimen.During a MST experiment, a temperature gradient is induced by an infrared laser. The directed movement of molecules through the temperature gradient is detected and quantified using either covalently attached or intrinsic fluorophores. By combining the precision of fluorescence detection with the variability and sensitivity of thermophoresis, MST provides a flexible, robust and fast way to dissect molecular interactions.In this review, we present recent progress and developments in MST technology and focus on MST applications beyond standard biomolecular interaction studies. By using different model systems, we introduce alternative MST applications – such as determination of binding stoichiometries and binding modes, analysis of protein unfolding, thermodynamics and enzyme kinetics. In addition, wedemonstrate the capability of MST to quantify high-affinity interactions with dissociation constants (Kds) in the low picomolar (pM) range as well as protein–protein interactions in pure mammalian cell lysates.

Ab initio calculations of molecular properties of low–lying electronic states of 2–cyclopenten–1–one – link with biological activity

Geometries, vibrational frequencies, vertical and adiabatic excitation energies, dipole moments and dipole polarizabilities of the ground and the three lowest electronic excited states, S₁(n, π*), T₁(n, π*), and T₂(π, π*) of the 2-cyclopenten-1-one molecule (2CP) were calculated at the CCSD and CCSD(T) levels of approximation. Our results indicate that two triplets T₁(n, π*) and T₂(π, π*) are lying very close each to other, while the singlet S₁(n, π*) is well above them. There are dramatic changes in dipole moments for (n, π*) excited states in respect to the ground state. On the other hand the T₂(π, π*) state has a similar dipole moment as the ground state. These changes can be interpreted within the MO picture using electrostatic potential maps and changes in model IR spectra. Our CCSD(T) dipole moment data for the ground state and almost isoenergetic triplets T₁(n, π*) and T₂(π, π*) are 1.469 a.u., 0.551 a.u., and 1.124 a.u., respectively. Dipole polarizabilities of investigated excited states are much less affected by electron excitations than dipole moments. These are the first dipole moment and polarizability data of 2CP in the literature. The changes of molecular properties upon excitation to S₁(n, π*) and T₁(n, π*) correlate with the experimental data on the biological activity of 2CP related to the α, β-unsaturated carbonyl group.

Axial ligand influence on geometries, charge distributions and electronic structures of iron tetraazamacrocycle [Fe (II)TIM(X)(Y)] 2+ complexes assessed by Density Functional Theory

We employed the Density Functional Theory along with small basis sets, B3LYP/LANL2DZ, for the study of FeTIM complexes with different pairs of axial ligands (CO, H 2O, NH 3, imidazole and CH 3CN). These calculations did not result in relevant changes of molecular quantities as bond lengths, vibrational frequencies and electronic populations supporting any significant back-donation to the carbonyl or acetonitrile axial ligands. Moreover, a back-donation mechanism to the macrocycle cannot be used to explain the observed changes in molecular properties along these complexes with CO or CH 3CN. This work also indicates that complexes with CO show smaller binding energies and are less stable than complexes with CH 3CN. Further, the electronic band with the largest intensity in the visible region (or close to this region) is associated to the transition from an occupied 3 d orbital on iron to an empty π ∗ orbital located at the macrocycle. The energy of this Metal-to-Ligand Charge Transfer (MLCT) transition shows a linear relation to the total charge of the macrocycle in these complexes as given by Mulliken or Natural Population Analysis (NPA) formalisms. Finally, the macrocycle total charge seems to be influenced by the field induced by the axial ligands.

Stimuli‐responsive polymers in the 21st century: Elaborated architecture to achieve high sensitivity, fast response, and robust behavior

AbstractLife is polymeric in its essence. The living cell contains a range of biopolymers such as proteins, carbohydrates, and nucleic acids. The cells are often compartmentalized via membranes that are composed of lipids. These are small molecules, but they spontaneously aggregate into supermolecular structures. The building blocks of these lipids are among others fatty acids, structures built from methylene oligomers. Biopolymers are sensitive to external stimuli. There are examples where the molecules show a highly non‐linear response to external stimuli. This is seen as moderate changes in structural properties in response to changes in an external parameter until a critical point is reached where a dramatic change in molecular properties takes place upon an incremental change in the external conditions. After the transition, the system responds poorly to further changes. Such non‐linear responses contribute to dramatic cooperative conformational changes leading to strong effects in the biological system. The strong response is an integrated effect of many weak interactions, and it is the cooperativity between all these interactions that are the driving forces for processes occurring in such systems. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2011

Biochemical Changes of Hemoglobin and Osmotic Fragility of Red Blood Cells in High Fat Diet Rabbits

The aim of this study was to assess the effects of hyperlipidemia on auto-oxidation rate of hemoglobin (Hb; absorbance at 630 nm versus time), Hb derivatives and osmotic fragility of Red Blood Cells (RBCs). These parameters were measured in twenty five 12-week-old male New Zealand white rabbits fed on a High Fat Diet (HFD) for a feeding period of 10 weeks. We found that Hb concentration and RBC count were significantly decreased while white blood cell and platelet counts were significantly increased in HFD rabbits compared with control rabbits. The Total Cholesterol (TC) was significantly increased (p < 0.01) in HFD rabbits compared with control rabbits with percentage normalized change of 1198% and Low Density Lipoprotein Cholesterol (LDLC) significantly increased (p < 0.01) in HFD rabbits compared with control rabbits with percentage normalized change of 1591%. In HFD rabbits, oxyhemoglobin (HbO2) percentage was significantly decreased while met-hemoglobin (Met-Hb) percentage was significantly increased compared with control rabbits. The auto-oxidation rate was significantly higher in HFD rabbits compared with controls. Hyperlipidemia induced an increase in the osmotic fragility of RBCs and a decrease in their membrane elasticity compared with controls. This study suggests that hyperlipidemia may produce reactive oxygen species and other free radicals which increase the auto-oxidation rate of Hb and promote the conversion of HbO2 and the fractions of unstable Hb molecules to Met-Hb and carboxyhemoglobin. Increased platelet activation in hyperlipidemic rabbits may be of pathophysiological importance for the progression of atherosclerosis and thromboembolic complications. The increase in osmotic fragility of RBCs may be attributed to the disturbance of ionic motion through the membrane and the change in molecular properties of the membrane macromolecules.

Fluorophores as Optical Sensors for Local Forces

The main aim of this study is to investigate correlations between the impact of an external mechanical force on the molecular framework of fluorophores and the resultant changes in their fluorescence properties. Taking into account previous theoretical studies, we designed a suitable custom-tailored oligoparaphenylenevinylene derivative (OPV5) with a twisted molecular backbone. Thin foils made of PVC doped with 100 nM OPV were prepared. By applying uniaxial force, the foils were stretched and three major optical effects were observed simultaneously. First, the fluorescence anisotropy increased, which indicates a reorientation of the fluorophores within the matrix. Second, the fluorescence lifetime decreased by approximately 2.5% (25 ps). Finally, we observed an increase in the emission energy of about 0.2% (corresponding to a blue-shift of 1.2 nm). In addition, analogous measurements with Rhodamine 123 as an inert reference dye showed only minor effects, which can be attributed to matrix effects due to refractive index changes. To relate the observed spectroscopic changes to the underlying changes in molecular properties, quantum-chemical calculations were also performed. Semiempirical methods had to be used because of the size of the OPV5 chromophore. Two conformers of OPV5 (C(2) and C(i) symmetry) were considered and both gave very similar results. Both the observed blue-shift of fluorescence and the reduced lifetime of OPV5 under tensile stress are consistent with the results of the semiempirical calculations. Our study proves the feasibility of fluorescence-based local force probes for polymers under tension. Improved optical sensors of this type should in principle be able to monitor local mechanical stress in transparent samples down to the single-molecule level, which harbors promising applications in polymer science and nanotechnology.

Optical Detection of Thymine Dinucleoside Monophosphate and Its cis-syn Photodimer by Inorganic Nanoparticles

The Watson-Crick DNA double helix is an averaged ideal of multitudinous natural sequence-directed local structural deviations. By effectively derailing normal cellular physiological processes, damaged bases can induce noncanonical irregularities in the local structure of DNA if not efficiently repaired. Pyrimidine bases, especially thymine, are prone to dimerization when exposed to ultraviolet light. A [2 + 2] photocyclo-addition between adjacent thymine bases predominantly produces the cis-syn photodimer. These lesions, implicated in skin cancer, bend DNA by approximately 30 degrees due to their structural and conformational changes. Such changes in molecular properties can be detected by differential quenching of CdS nanoparticle luminescence and by surface-enhanced Raman scattering spectroscopy on metal nanoparticle substrates.

Ageing of elastomers: a molecular approach based on rheological characterization

The relationship between chemical changes and changes of molecular properties of elastomeric materials through thermo-oxidation has been evaluated. Scission and recombination reactions compete during oxidative ageing. In the case of natural rubber, the molecular evolution exhibits a dual process, whereas, rapid crosslinking occurs from the beginning of the thermo-oxidation of EPDM. A chemical change has been simultaneously detected by FTIR for the two kinds of diene materials. These specific behaviours are compared to those upon photo-oxidation. No difference is recorded for NR. In contrast, the chronology of events depends on the process of oxidative ageing in case of EPDM.

Novel self-assembled monolayers of dipolar ruthenium(III/II) pentaammine(4,4'-bipyridinium) complexes on ultrathin platinum films as redox molecular switches.

We report the first example of a reversible redox-molecular switch based on dipolar ruthenium(III/II) pentaammine(4,4'-bipyridinium) complexes self-assembled on an optically transparent metal electrode, whose change in molecular properties can be simply detected by transmission spectroscopy with a conventional spectrophotometer.

The Effect of Substituents on Pyridinium Cation Formation on Pt(110)

In a recent paper we found that pyridinium cations (C5H5NH+) form during the coadsorption of pyridine and hydrogen on Pt(110) in UHV. In this paper the coadsorption of hydrogen and 2- or 3-fluoropyridine is examined with EELS to see how changes in molecular properties affect the stability of the ions. We find fluoropyridinium cations (C5H4FNH+) can form when 2-fluoro- or 3-fluoropyridine is adsorbed on a hydrogen precovered Pt(110) surface. However, the ion concentration is much lower with the fluorinated pyridines than with pyridine as expected since the proton affinity of the substituted pyridines is much lower than that of pyridine. Detailed analysis shows that the trends in the data cannot be explained by simply considering the variations in the proton affinity. Instead it appears that the strength of the pairwise repulsions between adjacent cations on the Pt(110) surface plays a key role in the stability of the cations.

Regulation of cellular and molecular functions by protein phosphorylation

Modification of proteins by phosphorylation is the major general mechanism by which many cellular functions in eukaryotic cells such as cell division, malignant transformation, differentiation, signal transduction etc. are controlled by external physiological stimuli. At the molecular level protein phosphorylation-dephosphorylation can alter various properties of the substrate molecules such as enzymatic activity, sub-Cellular location, ligand binding, interaction with other proteins, DNA binding and some other functional properties. The changes in molecular properties of proteins brought about by protein phosphorylation play a critical role in regulating various cellular functions.

Understanding relativistic effects of chemical bonding

To elucidate the physical origin of relativistic changes of molecular properties, exact theorems, perturbation theory, and Hartree-Fock-Slater-Pauli calculations are exploited. The relativistic molecular virial theorem offers insight into the relativistic and nonrelativistic, kinetic, and potential energy contributions to the bond energy. In general, there exist two contributions to the relativistic correction of a molecular property: the relativistic change at the nonrelativistic equilibrium geometry and the change of the nonrelativistic property due to the relativistic change of the equilibrium geometry. Sometimes the first and sometimes the second contribution is the dominant one. Accurate numerical results for H+2-like systems are obtained using direct relativistic double perturbation theory. In some cases, near-degenerate perturbation theory is mandatory. Relativistic changes of chemical bond energies are often proportional to the density change in the K-shell when the bond is formed. Relativistic corrections to many properties (and also to the 1s2-correlation energy) are often proportional to Z2α2. © 1996 John Wiley & Sons, Inc.

Theoretical analysis of the structural and chemical reactivity properties of the schistosomicidal drug niridazole

A theoretical quantum mechanical analysis of the structural, conformational and reactivity properties of the schistosomicidal drug niridazole is presented. The computations are carried out in the CNDO/2 approximation including full molecular geometry optimization and modellization of the solvent effect. The change in molecular properties when the molecule approaches a macromolecular receptor is simulated with decreasing values for the dielectric constant of the medium. In addition, the reactivity properties of niridazole are analyzed within the frontier orbital approximation. The structural analysis of the optimized geometries reveals a planar structure for the nitro group and the thiazole ring whereas the imidazolidinone ring is found to be non planar. The conformational analysis shows that the flexibility of the molecule, measured by the barriers to rotation of the imidazolidinone ring against the thiazole ring, increases greatly when the molecule approaches to a macromolecular receptor. Our reactivity results are in agreement with the experimental data and they support the hypothesis that the metabolic activation of niridazole in the schistosome involves a nucleophilic attack. The nitro group and some selected positions on the thiazole ring are the preferred points for this attack.

Mechanisms of photo-induced vitreous liquefaction.

To understand the mechanisms of photo-induced vitreous liquefaction, this study investigated the effects of free radicals on collagen and hyaluronic acid (HA). Bovine vitreous collagen or HA was irradiated by visible light in the presence of riboflavin (RF) as a photosensitizer. The changes in the molecular weight of collagen and HA were monitored by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and high-performance liquid chromatography, respectively. Free radicals were shown to cause an increase in the high-molecular-weight components and insolubilization of the vitreous collagen and a decrease in the molecular weight of HA. The change in molecular properties of the vitreous collagen could be attributed to extensive crosslinks of the molecules. Since RF is present in the vitreous, which is irradiated by visible light over a lifetime, both cross-links of vitreous collagen and degradation of HA may contribute to age-related vitreous liquefaction.

An AM1-SCRF approach to the study of changes in molecular properties induced by solvent

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAn AM1-SCRF approach to the study of changes in molecular properties induced by solventF. J. Luque, M. J. Negre, and Modesto OrozcoCite this: J. Phys. Chem. 1993, 97, 17, 4386–4391Publication Date (Print):April 1, 1993Publication History Published online1 May 2002Published inissue 1 April 1993https://doi.org/10.1021/j100119a022RIGHTS & PERMISSIONSArticle Views98Altmetric-Citations82LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (1 MB) Get e-Alerts