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PubMed2006

New paramagnetic supramolecular adducts for MRI applications based on non-covalent interactions between Gd(III)-complexes and beta- or gamma-cyclodextrin units anchored to chitosan.

Gd(III) complexes are used as magnetic resonance imaging (MRI) contrast agents because they greatly enhance the relaxation rate of water protons of tissues in which they distribute, an effect that is much more marked if the paramagnetic complex is part of a macromolecular system. Furthermore applications in molecular imaging, require that as many units of contrast agent as possible be directed to the site of interest. To this end we synthesised a polymer made of chitosan functionalized with beta- and gamma-cyclodextrins (CDs) that is able to form high-affinity adducts with suitably functionalized Gd(III) complexes. beta- and gamma-CDs were first treated with maleic anhydride to afford 6-monosubstituted derivatives that reacted regioselectively with the amino groups of chitosan. Reaction times and yields were markedly improved by carrying out these reactions under high-intensity ultrasound or microwave irradiation. Compared to the CD monomers, beta- and gamma-CD-chitosan adducts show large increases both in terms of their binding affinity towards Gd(III) complexes and in relaxivity values and they appear promising carriers for the in vivo vehiculation of Gd(III) complexes.

Chitosan↗
PubMed2006

Revisiting the initial rate approximation in kinetic NOE measurements.

The nuclear Overhauser effect (NOE) is undoubtedly one of the most useful tools in NMR spectroscopy and is widely used in solving structural and conformational problems of small organic molecules and macromolecular systems alike. In particular, measurement of the kinetics of the NOE, often facilitated by selective 1D NOE buildup experiments, can generate invaluable quantitative distance information for the molecule being investigated. In practice, analysis of such kinetic NOE data routinely assumes a first-order approximation of the initial buildup rate. However, often times such an approximation holds true only for the shortest mixing times. As shown by Macura and others, the linear range of the NOE buildup obtained from 2D NOESY and exchange experiments can be substantially extended by simply scaling the NOE cross-peaks against the corresponding diagonal peaks. In this note, we demonstrate through a detailed analysis that the same approach can be applied to the analysis of 1D NOE data obtained with the DPFGSE NOE pulse sequence, one of the most widely used selective 1D NOE experiments today. We show that this approach allows the inclusion of data points acquired with much longer mixing times in the analysis and thus considerably improves the accuracy of the measured cross-relaxation rates and internuclear distances, while considerably simplifying the data analysis. Similar results can be obtained for the rotating frame DPFGSE ROE experiment.

Journal Article↗
PubMed2006

Steady-state fluorescence quenching applications for studying protein structure and dynamics.

Fluorescence quenching methods are useful to obtain information about the conformational and/or dynamic changes of proteins in complex macromolecular systems. In this review steady-state methods are described and the data interpretation is thoroughly discussed. As a special case of fluorescence quenching mechanism, fluorescence resonance energy transfer (FRET) phenomenon is also presented. Application of a FRET based method to characterize the temperature dependence of the flexibility of protein matrix is clearly demonstrated.

Acrylamide↗
PubMed2006

A study of collective atomic fluctuations and cooperativity in the U1A-RNA complex based on molecular dynamics simulations.

Cooperative interactions play an important role in recognition and binding in macromolecular systems. In this study, we find that cross-correlated atomic fluctuations can be used to identify cooperative networks in a protein-RNA system. The dynamics of the RRM-containing protein U1A-stem loop 2 RNA complex have been calculated theoretically from a 10 ns molecular dynamics (MD) simulation. The simulation was analyzed by calculating the covariance matrix of all atomic fluctuations. These matrix elements are then presented in the form of a two-dimensional grid, which displays fluctuations on a per residue basis. The results indicate the presence of strong, selective cross-correlated fluctuations throughout the RRM in U1A-RNA. The atomic fluctuations correspond well with previous biophysical studies in which a multiplicity of cooperative networks have been reported and indicate that the various networks identified in separate individual experiments are fluctuationally correlated into a hyper-network encompassing most of the RRM. The calculated results also correspond well with independent results from a statistical covariance analysis of 330 aligned RRM sequences. This method has significant implications as a predictive tool regarding cooperativity in the protein-nucleic acid recognition process.

Amino Acid Sequence↗
PubMed2006

Conformer generation under restraints.

Conformational sampling by direct optimization of an all-atom energy function is ineffective and inefficient because of the ruggedness of the energy landscape. Discrete sampling schemes represent an attractive alternative for generating ensembles of conformers consistent with spatial restraints derived from empirical data. Conformational sampling is becoming increasingly important for structure prediction as the bottleneck in accurate prediction shifts from energy functions to the methods used to find low-energy conformers. Experimental structure determination remains a perennial challenge as investigators tackle larger macromolecular systems, and begin to incorporate more complete descriptions of uncertainty, heterogeneity and dynamics into their models. Computational approaches that combine dense, discrete sampling with all-atom energy evaluation and refinement may help to overcome the remaining barriers to solving these problems.

Algorithms↗
PubMed2001

Modern physicochemical research on Langmuir monolayers.

Recent developments in characterising Langmuir monolayers of a variety of film-forming materials and employing several physicochemical techniques are reviewed. The extension of the LB method to non-amphiphilic substances, especially macromolecular systems, has increased the need of a thorough understanding of Langmuir film properties, which requires characterising techniques that provide complementary information. Since there is vast literature in the subject, only selected examples are given of results that illustrate the potential of the techniques discussed.

Chemistry, Physical↗
PubMed1981

Analysis of data from the analytical ultracentrifuge by nonlinear least-squares techniques.

Least-squares analysis of experimental data from the analytical ultracentrifuge is discussed in detail, with particular attention to the use of interference optics in studying nonideal self-associating macromolecular systems. Several samples are given that describe the application of the technique, the expected precision of the results, and some of its limitations. A FORTRAN IV computer program is available from the authors.

Computers↗
PubMed1997

Influence of the membrane potential on the free energy of an intrinsic protein.

A modified Poisson-Boltzmann equation is developed from statistical mechanical considerations to describe the influence of the transmembrane potential on macromolecular systems. Using a Green's function formalism, the electrostatic free energy of a protein associated with the membrane is expressed as the sum of three terms: a contribution from the energy required to charge the system's capacitance, a contribution corresponding to the interaction of the protein charges with the membrane potential, and a contribution corresponding to a voltage-independent reaction field free energy. The membrane potential, which is due to the polarization interface, is calculated in the absence of the protein charges, whereas the reaction field is calculated in the absence of transmembrane potential. Variations in the capacitive energy associated with typical molecular processes are negligible under physiological conditions. The formulation of the theory is closely related to standard algorithms used to solve the Poisson-Boltzmann equation and only small modifications to current source codes are required for its implementation. The theory is illustrated by examining the voltage-dependent membrane insertion of a simple polyalanine alpha-helix and by computing the electrostatic potential across a 60-A-diameter sphere meant to represent a large intrinsic protein.

Algorithms↗
PubMed2001

Molecular and crystal structures of N-aryl-beta-D-glycopyranosylamines from mannose and galactose.

The molecular and crystal structures of 12 N-aryl-beta-D-glycopyranosylamines have been determined by X-ray crystallography. Six of these are mannose derivatives, the N-p-bromophenyl (1), N-p-tolyl (2), N-m-chlorophenyl (3), N-p-methoxyphenyl (4), N-o-chlorophenyl (5), and N-o-tolyl (6) derivatives that are formed by reaction with the corresponding substituted anilines. The remaining six are galactose derivatives, the N-phenyl (7), N-p-chlorophenyl (8), N-p-bromophenyl (9), N-p-iodophenyl (10), N-p-nitrophenyl (11) and N-p-tolyl (12), derivatives prepared similarly. Compounds 1-3 assume the same packing arrangement. Compounds 4, 5, and 6 assume unique packing arrangements, although that assumed by 4 is closely related to that assumed by 1-3. Compounds 7-11 assume the same packing arrangement; that assumed by 12 is closely related to that assumed by 7-11. That the same packing arrangements can be maintained in spite of substantial changes in the electronic and steric nature of the substituent on the aryl ring reflects the strength of the hydrogen bond network connecting the monosaccharide portions of the molecules in the solid state. A hydrogen bonding motif found in all six mannose structures is a mutual interaction between translationally related molecules involving O-3-H...O-5 and O-6-H...O-4 hydrogen bonds. The recurrence of this motif throughout this group of mannosylamines suggests that it is an especially favorable interaction that might be expected to occur also in related macromolecular systems.

Amino Sugars↗
PubMed2003

How large are the volume changes accompanying protein transitions and binding?

We present a simple model to describe volume changes accompanying protein folding and binding events. The model enables one to resolve the changes in volume accompanying conformational transitions of proteins as well as association of proteins with other molecules in terms of the intrinsic, thermal and interaction (hydration) contributions. The thermal contribution to protein volume results from thermally activated mutual vibrational motions of contacting solute and solvent molecules. Our calculations suggest that near zero volume changes accompanying protein folding and binding events reflect compensation between significant changes in the intrinsic, thermal and interaction terms. We have quantitatively estimated these terms as a function of the protein's molecular weight and degree of its unfolding. Results described in this work lay foundation for more reliable and physically justified interpretations of volumetric data on protein folding and binding events. We also discuss potential ways of extending applications of our model to analyzing other macromolecular systems and events, including drug-DNA and protein-DNA interactions and helix-to-helix and helix-to-coil transitions of nucleic acids.

Animals↗
PubMed2000

Role of myofilaments and calcium handling in left ventricular relaxation.

Myocardial relaxation is governed by the interplay of two macromolecular systems: (1) myofilaments and (2) calcium extruding pumps/exchangers. In myocardium from failing hearts, both systems act more slowly than normal, and cause relaxation to decelerate, which may impede early rapid filling and can often limit cardiac pumping ability--especially during exercise. Gene-based therapy to augment sluggish SERCA pumps is a possibility being currently investigated in research laboratories. In normal myocardium, the rate of dissociation of myosin crossbridges sets the rate of relaxation. In this case, relaxation is characterized by two features: (1) load-dependence and (2) displacement-dependence. Load-dependence derives from cooperative mechanisms acting among ensembles of crossbridges and myofilament regulatory proteins (troponin, tropomyosin); it allows contraction to be prolonged when more crossbridges are attached and mutually support each other. The rate of relaxation can still be rapid, however, as this cooperative system begins to collapse. Displacement-dependence is more important later in contraction, because tenuous crossbridge attachments cannot easily re-form after being disrupted when myofilaments slide along each other. Myofilaments control normal relaxation because the calcium extruding systems reduce calcium to near diastolic levels relatively early; however, when the relative timing of crossbridge dissociation versus calcium sequestration is altered, and calcium uptake is slowed (relative to crossbridges), then removal of calcium can become rate limiting instead. In this case, load- and displacement-dependence are less marked. Both the timing of calcium removal and the sensitivity of the myofilaments to calcium affect relaxation timing.

Actin Cytoskeleton↗
PubMed1998

Water vapor sorption by peptides, proteins and their formulations.

The interactions of pharmaceutical peptides, proteins and their formulations with environmental water vapor are reviewed. Particular attention is paid to the importance of the physical structure and chemical diversity of peptides and proteins, and comparisons are made with the mechanisms of water vapor sorption by synthetic macromolecular systems. The influences of formulation processes and additives are also considered and suggestions made for future areas of research.

Adsorption↗
PubMed2003

X-filtering for a range of coupling constants: application to the detection of intermolecular NOEs.

A new method for heteronuclear X-filtering is presented, which relies on repetitive applications of 90 degrees (1H)-tau(1/41J(HC))-180 degrees (1H,13C)-tau(1/41J(HC))-90 degrees (1H,13C)-PFG building blocks employing gradient-mediated suppression of magnetization built up for directly heteronuclear coupled protons. Thereby, a range of heteronuclear coupling constants can be suppressed by varying the delays of scalar coupling evolution both within and between individual transients. To achieve efficient destruction of 13C-coupled protons in macromolecular systems, the scalar coupling evolution delays were optimized using simulated annealing by including transverse relaxation effects. With a combination of regular hard pulses, delays and pulsed field gradients only, this method yields sufficient X-filtering to allow the observation of intermolecular nuclear overhauser effects in a molecular complex consisting of a 13C, 15N double-labeled, and an unlabeled protein. This is achieved by exciting magnetization of 12C- and 14N-bound protons and detecting 13C-bound 1H magnetization in a 3D 13C-filtered, 13C-edited NOESY-HSQC experiment. The method is tested on the 18 kDa homodimeric bacterial antidote ParD.

Carbon Isotopes↗
PubMed2003

Thermal dissociation of multimeric protein complexes by using nanoelectrospray mass spectrometry.

The behavior of macromolecular systems at different temperatures is often crucial to their biological activity and function. While heat-induced changes of individual proteins are readily monitored by a number of spectroscopic methods, changes in noncovalent complexes of biomolecules are more challenging to interpret. Nanoelectrospray mass spectrometry is becoming increasingly powerful in the study of large noncovalent complexes, and here we describe the design, characterization, and application of a novel probe that allows the thermocontrol of the solution in the electrospray capillary. The transition temperature for the unfolding of the protein lysozyme is readily obtained and correlates closely with that measured by fluorescence spectroscopy, thereby demonstrating the validity of this approach. We apply this technique to the study of the 200-kDa complex of the small heat shock protein TaHSP16.9, revealing both its dissociation into suboligomeric species and an increase in its size and polydispersity at elevated temperatures. In contrast, gas-phase activation of this complex is also carried out and yields a dissociation pathway fundamentally different from that observed for thermal activation in solution. As such, this probe allows the study of the reversible heat-induced changes of noncovalent complexes in a biologically relevant manner.

Animals↗
PubMed1992

Protein folding: assignment of the energetic changes of reversible chemical modifications to the folded or unfolded states.

Reversible chemical modifications of a series of single cysteine-containing variants of T4 lysozyme combined with thermal denaturation studies have been used to study the effects of these modifications on the stability of the protein. This allows dissection of the energetic effects of the modification on both the native and denatured states of this protein. At some sites modifications with various chemical reagents have essentially no effect on the stability of the protein, while at others, substantial changes in stability are observed. For example, chemical modification of cysteine at site 146 by cystamine (+NH3CH2CH2SSCH2-CH2NH3+) to form the mixed disulfide lowers the stability of the protein by about 1.1 kcal/mol. The reduction in the free energy of folding caused by the chemical modification is attributed to the destabilization of native state (0.9 kcal/mol), with only a relatively small effect from stabilization of the denatured state (0.2 kcal/mol). Chemical modifications of T4 lysozyme at site 146 with various chemical reagents show that the stability of the protein is lowered by a positively charged group and is relatively independent of the size of the side chains. This approach allows the investigation of the thermodynamic consequences of the reversible insertion of a wide variety of chemical entities at specific sites in proteins and, most importantly, allows dissection of the contribution of the chemical modifications to both the folded and unfolding states. It can be applied to almost any suitable macromolecular system.

Buffers↗
PubMedDate not supplied

QCODES - fast topological descriptors for macromolecules.

A fast iterative algorithm to obtain topological atomic and molecular descriptors, called Qcodes, is presented in this work. Its linear time dependence with the size of the structures and low memory requirement allows practical use for small molecules as well as macromolecular systems. The descriptors are unique and are able to sense small topological changes in atom's neighborhood. These properties make them suitable as atom and molecular identifiers to be used in database searching, force field atom typing, isomorphism, and automorphism algorithms. Examples of descriptors, their convergence behavior, sensitivity, ambiguity, and algorithm's performance are shown in this paper.

Journal Article↗
PubMed2001

Solid-state and solution properties of the lanthanide complexes of a new heptadentate tripodal ligand: a route to gadolinium complexes with an improved relaxation efficiency.

The tripodal ligand (alpha,alpha',alpha' 'nitrilotri(6-methyl-2-pyridinecarboxylic acid)) (H(3)tpaa) forms a Gd(III) complex which has a relaxivity (r(1p) = 13.3 mM(-1) s(-1) at 25 degrees C and at 60 MHz) remarkably higher than those of the currently clinically used contrast agents based on octacoordinate polyaminocarboxylate complexes (3.5-4.7 mM(-1) s(-1)) and a reasonably good thermodynamic stability. The crystal structure of the ligand and of its La, Nd, Eu, Gd, Tb, Ho, Tm, Yb, and Lu complexes have been determined by X-ray crystallography. The neutral H(3)tpaa molecule adopts, in the solid state, a preorganized tripodal conformation in which the three H(3)tpaa arms are located on the same side of the molecule, ready to bind a metal ion in a heptadentate coordination mode. The structures of the Ln(III) complexes vary along the series for their nuclearity and number of water molecules coordinated to the metal, and a tetrameric structure is observed for the La(3+) ion (9- and 10-coordinate metal centers), dimeric structures are formed from the Nd(3+) ion through the Yb(3+) ion (9-coordinate), and a monomeric structure results for Lu(3+) (8-coordinate). The relaxivity studies presented here suggest that the high relaxivity of the Gd(tpaa) complex is mainly the consequence of a shorter bound water proton-Gd(III) distance associated with a probable water coordination equilibrium between tris(aqua) and bis(aqua) complexes, giving raise to a mean number of coordinated water molecules q > 2. Both effects are strongly related to the ligand flexibility, which allows for a large volume available for water binding. The observed rapid water exchange rate is probably due to the presence of a low-energy barrier between 10-, 9-, and 8- coordinate geometries. Although the low solubility of the Gd complex of tpaa prevents its practical application as an MRI contrast agent, the straightforward introduction of substituents on the pyridine rings allows us to envisage ligands with a higher water solubility, containing functional groups leading to macromolecular systems with very high relaxivity.

Journal Article↗
PubMed2002

How does internal motion influence the relaxation of the water protons in Ln(III)DOTA-like complexes?

Taking advantage of the Curie contribution to the relaxation of the protons in the Tb(III) complex, and the quadrupolar relaxation of the 17O and 2H nuclei on the Eu(III) complex, the effect of the internal motion of the water molecule bound to [Ln(DOTAM)(H2O)]3+ complexes was quantified. The determination of the quadrupolar coupling constant of the bound water oxygen chi(Omicron)(1 + eta(Omicron)2/3)1/2 = 5.2 +/- 0.5 MHz allows a new analysis of the 17O and 1H NMR data of the [Gd(DOTA)(H2O)]- complex with different rotational correlation times for the Gd(III)-O(water) and Gd(III)-H(water) vectors. The ratio of the rotational correlation times for the Ln(III)-H(water) vector and the overall rotational correlation time is calculated tau(RH)/tau(RO) = 0.65 +/- 0.2. This could have negative consequences on the water proton relaxivity, which we discuss in particular for macromolecular systems. It appears that the final effect is actually attenuated and should be around 10% for such large systems undergoing local motion of the chelating groups.

Journal Article↗