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PubMed2005

Conformational dynamics of the nicotinic acetylcholine receptor channel: a 35-ns molecular dynamics simulation study.

The nicotinic acetylcholine receptor (AChR) is the paradigm of ligand-gated ion channels, integral membrane proteins that mediate fast intercellular communication in response to neurotransmitters. A 35-ns molecular dynamics simulation has been performed to explore the conformational dynamics of the entire membrane-spanning region, including the ion channel pore of the AChR. In the simulation, the 20 transmembrane (TM) segments that comprise the whole TM domain of the receptor were inserted into a large dipalmitoylphosphatidylcholine (DPPC) bilayer. The dynamic behavior of individual TM segments and their corresponding AChR subunit helix bundles was examined in order to assess the contribution of each to the conformational transitions of the whole channel. Asymmetrical and asynchronous motions of the M1-M3 TM segments of each subunit were revealed. In addition, the outermost ring of five M4 TM helices was found to convey the effects exerted by the lipid molecules to the central channel domain. Remarkably, a closed-to-open conformational shift was found to occur in one of the channel ring positions in the time scale of the present simulations, the possible physiological significance of which is discussed.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1977

Proton magnetic resonance study of conformational dynamics, coordianted internal motions, and chemical shifts of tocinamide.

All proton magnetic resonance lines of the NH-CHalpha-CH2beta fragments of five amino acid residues of the heterodetic peptide, tocinamide, have been analyzed, including reassigment of certain NH, CHalpha, and CH2beta resonances. The 1H NMR spectral parameters evaluated from this analysis include (a) all chemical shifts, (b) (3JNHCH), (3Jalpha beta), and (2Jbeta beta) values, and (c) temperature dependencies of these coupling constants and chemical shifts--the latter includes aliphatic and aromatic CH protons. The (3Jalpha beta) coupling constants yielded Calpha-Cbeta rotamer populations, Pi, for five residues and these were used to explore conformational dynamics and coordinated internal motions of tocinamide. The rotamer populations and their temperature dependencies established, (1) that all Calpha-Cbeta bonds exhibit extensive internal rotation; (2) that rotamer preferences exist for every residue; (3) that the 162 conformations possible for completely free rotation around every bond of the Calpha1-Cbeta1-S1-S6-Cbeta6-Calpha6 disulfide fragment can be reduced to two or three if the concept of coordinated internal motion is introduced. We reject the possibility of a frozen conformation for the Cys1-Cys6 fragment in the eclipsed, staggered, or nonclassical rotamer states and propose the following possibilities: (a) three classical rotamers populated in the ratio 60:25:15, (b) three nonclassical rotamers not differing by +/- 15 degrees from the classical values of 180 degrees, + 60 degrees, and -60 degrees, or (c) two nonclassical but noneclipsed rotamers with a third rotamer essentially zero, and (4) that the Calpha-Cbeta rotamer populations of the Tyr2-Cys1-S-S-Cys6 fragment are consistent with coordinated internal motions of the Calpha-Cbeta bonds of all three residues. The existence of temperature coefficients, deltadelta/deltaT, POF +/- 2 ppb/degrees C for aliphatic protons can be accounted for, in part, by postulating intrinsic rotamer chemical shifts which are temperature independent. Deltadelta/deltaT values should therefore be useful for investigating conformational dynamics. A further consequence of this interpretation is that greater care should be exercised in using deltadelta/deltaT values to assign hydrogen-bonded amide protons, especially when deltadelta/deltaT approximately -2 to -4 ppb/degrees C.

Amino Acids↗
PubMed1993

Conformational dynamics of cytochrome P-450cam as monitored by photoacoustic calorimetry.

Conformational transitions of cytochrome P-450cam following the dissociation of CO from the ferrous heme were investigated by using photoacoustic calorimetry. The effect of substrate association on the acoustic signal was also examined. Results show that the conformational dynamics of cytochrome P-450cam substrate-free protein occur faster than 10 ns, which is the time scale of the instrument response. The enthalpy and volume change for the dissociation reaction are 2.2 kcal mol-1 and 1.8 mL mol-1, respectively. Upon addition of camphor, the reaction is markedly slowed. An intermediate is formed whose lifetime is 130 ns at 17 degrees C. The overall enthalpy and volume changes are -15.9 kcal mol-1 and 10.3 mL mol-1, respectively. These results, together with published transient Raman spectra [Wells, A. V., Pusheng, L., Champion, P. M., Martinis, S. A., & Sligar, S. G. (1992) Biochemistry 31, 4384-4393] suggest that camphor leaves the heme pocket concomitant with the photoinduced expulsion of CO into the solvent and induces a considerable conformational change in the protein.

Calorimetry↗
PubMed2002

Ultrafast spectroscopy reveals subnanosecond peptide conformational dynamics and validates molecular dynamics simulation.

Femtosecond time-resolved spectroscopy on model peptides with built-in light switches combined with computer simulation of light-triggered motions offers an attractive integrated approach toward the understanding of peptide conformational dynamics. It was applied to monitor the light-induced relaxation dynamics occurring on subnanosecond time scales in a peptide that was backbone-cyclized with an azobenzene derivative as optical switch and spectroscopic probe. The femtosecond spectra permit the clear distinguishing and characterization of the subpicosecond photoisomerization of the chromophore, the subsequent dissipation of vibrational energy, and the subnanosecond conformational relaxation of the peptide. The photochemical cis/trans-isomerization of the chromophore and the resulting peptide relaxations have been simulated with molecular dynamics calculations. The calculated reaction kinetics, as monitored by the energy content of the peptide, were found to match the spectroscopic data. Thus we verify that all-atom molecular dynamics simulations can quantitatively describe the subnanosecond conformational dynamics of peptides, strengthening confidence in corresponding predictions for longer time scales.

Computer Simulation↗
PubMed2001

Subpicosecond conformational dynamics of small peptides probed by two-dimensional vibrational spectroscopy.

The observation of subpicosecond fluctuations in the conformation of a small peptide in water is demonstrated. We use an experimental method that is specifically sensitive to conformational dynamics taking place on an ultrafast time scale. Complementary molecular-dynamics simulations confirm that the conformational fluctuations exhibit a subpicosecond component, the time scale and amplitude of which agree well with those derived from the experiment.

Computer Simulation↗
PubMed2000

The thermophilic esterase from Archaeoglobus fulgidus: structure and conformational dynamics at high temperature.

The esterase from the hyperthermophilic archaeon Archaeoglobus fulgidus is a monomeric protein with a molecular weight of about 35.5 kDa. The enzyme is barely active at room temperature, displaying the maximal enzyme activity at about 80 degrees C. We have investigated the effect of the temperature on the protein structure by Fourier-transform infrared spectroscopy. The data show that between 20 degrees C and 60 degrees C a small but significant decrease of the beta-sheet bands occurred, indicating a partial loss of beta-sheets. This finding may be surprising for a thermophilic protein and suggests the presence of a temperature-sensitive beta-sheet. The increase in temperature from 60 degrees C to 98 degrees C induced a decrease of alpha-helix and beta-sheet bands which, however, are still easily detected at 98 degrees C indicating that at this temperature some secondary structure elements of the protein remain intact. The conformational dynamics of the esterase were investigated by frequency-domain fluorometry and anisotropy decays. The fluorescence studies showed that the intrinsic tryptophanyl fluorescence of the protein was well represented by the three-exponential model, and that the temperature affected the protein conformational dynamics. Remarkably, the tryptophanyl fluorescence emission reveals that the indolic residues remained shielded from the solvent up to 80 degrees C, as shown from the emission spectra and by acrylamide quenching experiments. The relationship between enzyme activity and protein structure is discussed.

Archaeoglobus fulgidus↗
PubMed2004

Conformational dynamics of poly(acrylic acid). A study using surface plasmon resonance spectroscopy.

The conformational dynamics of poly(acrylic acid) induced by pH change is reported here. Poly(acrylic acid) immobilized on gold surface was exposed to pH changes, and the conformational changes thus induced were followed in real time using surface plasmon resonance spectroscopy. The temporal profile of the stretching-coiling phenomenon showed a minimum point, which was proposed to be arising due to the contradictory behavior of two different property changes in the polymeric system. Normally surface plasmon resonance (SPR) response would be a convoluted effect of the thickness and refractive index changes, but the behavior observed here, where the SPR response is predominantly governed by either one of the two, is unique and to the author's knowledge is a feature that is observed for the first time. Analysis of the kinetics of the angle change revealed that it takes longer for the polymer to stretch than it takes for it to collapse, with the kinetic rate constants varying by at least an order of magnitude. The SPR angle change as well as the kinetic constants increased linearly with molecular weight. Effect of Ca2+ was studied, and it was found that the polymer was locked in its conformation due to the binding of the multivalent cations.

Journal Article↗
PubMed1992

Dynamic conformations compared for IgE and IgG1 in solution and bound to receptors.

Dynamic conformations of two distinct immunoglobulin (Ig) isotypes, murine IgE and human IgG1, were examined with fluorescence resonance energy transfer measurements. The IgE mutant epsilon/C gamma 3* and the IgG1 mutant gamma/C gamma 3* each bind [5-(dimethylamino)naphthalen-1-yl]sulfonyl (DNS) in two identical antigen binding sites at the amino (N)-terminal ends of the Ig in the Fab segments. Eosin-DNS bound in these Fab sites served as the acceptor probe in these studies. Both Ig have a carboxy (C)-terminal domain (C gamma 3*) which contains genetically introduced cysteine residues. Modification of these cysteine sulfhydryls with fluorescein maleimide provided donor probes near the C-terminal ends of the Ig in the Fc segment. Energy transfer between the C-terminal and N-terminal ends was compared for these two Ig in solution and when they were found to their respective high-affinity receptors on plasma membranes: IgE-Fc epsilon RI on RBL cell membranes and IgG1-Fc gamma RI on U937 cell membranes. Previous energy-transfer measurements with these probes yielded an average end-to-end distance of 71 A for IgE in solution and 69 A for IgE bound to Fc epsilon RI, indicating that in both situations IgE is bent such that the axes of the Fab segments and the axis of the Fc segment do not form a planar Y-shape [Zheng, Shopes, Holowka, & Baird (1991) Biochemistry 30, 9125]. In the current study we found the average end-to-end distance for IgG1 in solution is 75 A and greater than or equal to 85 A for IgG1 bound to Fc gamma RI, suggesting an average bend conformation for IgG1 as well. The contributions of segmental flexibility to the average distances were assessed directly by measuring the efficiency of energy transfer as a function of variations in donor quantum yield caused by a collisional quencher and using these data to extract a Gaussian distribution of end-to-end distances. The distribution average (rho) and half-width (hw) were determined to be as follows: rho = 75 A, hw = 24 A for IgE in solution; rho = 71 A, hw = 12 A for IgE bound to Fc epsilon RI; and rho = 100 A, hw = 88 A for IgG in solution.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1998

Conformational dynamics and enzyme activity.

Conformational flexibility and structural fluctuations play an important role in enzyme activity. A great variety of internal motions ranging over different time scales and of different amplitudes are involved in the catalytic cycle. These different types of motions and their functional consequences are considered in the light of experimental data and theoretical analyses. The conformational changes upon substrate binding, and particularly the hinge-bending motion which occurs in enzymes made of two domains, are analyzed from several well documented examples. The conformational events accompanying the different steps of the catalytic cycle are discussed. The last section concerns the motions involved in the allosteric transition which regulates the enzyme activity.

Allosteric Regulation↗
PubMed1982

Conformational dynamics of a biologically active three-fragment complex of horse cytochrome c.

The conformational dynamics of a biologically active noncovalent complex containing three fragments, ferroheme fragment (1-25)H and apofragments (28-38) and [3H](56-104) [or [3H](39-104)], of horse cytochrome c has been studied with respect to kinetics and thermodynamics of dissociation. The rate of unfolding of the two-fragment complex ferro(1-25)H . (56-104) was also estimated. The results indicate that the ferrous three-fragment complex exhibits a higher frequency of dissociation-association with fragment (28-38) and a lower frequency of overall unfolding-folding at pH 7.0. In the presence of an excess of free (28-38) and below 30 degrees C, unfolding of the ferrous three-fragment complex appears to occur by activation to the transitional state without a large change in conformation, followed by virtually simultaneous dissociation of all three of the fragments [without going through the complex (1-25)H . (56-104), which is a major intermediate for folding]. Above 30 degrees C unfolding via the complex (1-25)H . (56-104) becomes detectable because the equilibrium between the two- and the three-fragment complex is highly temperature dependent. Thus, the relative probabilities of these two different ways of transition for unfolding are modulated by temperature. The observations suggest that the mode of activation of protein and hence the pathway for unfolding may vary depending on temperature. It is also suggested that the interatomic interactions binding the three fragments together in the ordered complex are linked to strengthen each other in the ground state.

Animals↗
PubMed1999

Solvent effects on conformational dynamics of Zn-substituted myoglobin observed by time-resolved hole-burning spectroscopy.

Equilibrium conformational fluctuation of Zn-substituted myoglobin (ZnMb) has been studied in the nanosecond to millisecond time region and 180-300 K temperature region by the time-resolved transient hole-burning spectroscopy. In this technique, the conformational fluctuation of the protein is observed as the temporal variation of the hole spectrum burned by irradiation of the laser pulse. ZnMb solution samples in various solvent conditions were prepared and investigated to elucidate the solvent effect on the conformational dynamics of Mb. The configuration coordinate model assuming the harmonic energy landscape has given a fairly good description of the time dependence of the hole spectra. The observed temporal behavior of both the hole shift and the hole broadening was well expressed by the same stretched exponential correlation function with a rather small and almost temperature-independent beta of 0.26. It was found that the correlation time tauc of the conformational fluctuation of ZnMb determined by this analysis depends linearly on the solvent viscosity regardless of the solvent composition and temperature. This means the almost 0 activation energy for the fluctuation process and can not be understood by simply assuming the Arrhenius-type crossing of the barriers separating the conformational substates. It is shown that this linear viscosity dependence of tauc, as well as the temperature-independent beta, is qualitatively explained in the framework of the hierarchically constrained dynamics (HCD) model [Palmer, R. G. et al. (1984) Phys. Rev. Lett. 53, 958-961] with the postulate that the dynamics in the lowest level in the HCD model corresponds in the actual system to the configuration fluctuations of the solvent molecules surrounding the protein.

Models, Chemical↗
PubMed2002

Stability and conformational dynamics of metallothioneins from the antarctic fish Notothenia coriiceps and mouse.

The structural properties and the conformational dynamics of antarctic fish Notothenia coriiceps and mouse metallothioneins were studied by Fourier-transform infrared and fluorescence spectroscopy. Infrared data revealed that the secondary structure of the two metallothioneins is similar to that of other metallothioneins, most of which lack periodical secondary structure elements such as alpha-helices and beta-sheets. However, the infrared spectra of the N. coriiceps metallothionein indicated the presence of a band, which for its typical position in the spectrum and for its sensitivity to temperature was assigned to alpha-helices whose content resulted in 5% of the total secondary structure of the protein. The short alpha-helix found in N. coriiceps metallothionein showed an onset of denaturation at 30 degrees C and a T(m) at 48 degrees C. The data suggest that in N. coriiceps metallothionein a particular cysteine is involved in the alpha-helix and in the metal-thiolate complex. Moreover, infrared spectra revealed that both proteins investigated possess a structure largely accessible to the solvent. The time-resolved fluorescence data show that N. coriiceps metallothionein possesses a more flexible structure than mouse metallothionein. The spectroscopic data are discussed in terms of the biological function of the metallothioneins.

Animals↗
PubMed2001

The effect of molecular confinement on the conformational dynamics of the native and partly folded state of apomyoglobin.

Inclusion in agarose gel significantly affects the conformational dynamics of native and acidic partly folded states of tuna apomyoglobin, a single tryptophan containing protein, as documented by frequency domain fluorometry investigations. The heterogeneity of the tryptophanyl emission decay increases on gel inclusion compared to that observed for free-in-solvent protein at both neutral and acidic pH, thus suggesting that the interconversion rate among conformational substates is somewhat reduced. The observation that this effect is much more pronounced for the partly folded state suggests that confined environments such as those existing in the living cells might favor the sequential folding process avoiding that structured intermediates rapidly convert into less structured ones.

Animals↗
PubMed2006

Allosteric regulation of the conformational dynamics of a cavitand receptor.

[reaction: see text] Inspired by allostery in nature, we synthesized cavitand 1 and investigated regulation of its conformational dynamics. Quantitative 1H NMR studies have revealed that the rate of the conformational isomerization of 1 can be modulated using the external addition of acid. As 1 maintains its vase-like conformation in an acidic environment, ample opportunities for controlling the kinetics of molecular recognition, and thus reactivity, in this and related receptors have arisen.

Journal Article↗
PubMed2006

The Ig doublet Z1Z2: a model system for the hybrid analysis of conformational dynamics in Ig tandems from titin.

Titin is a gigantic elastic filament that determines sarcomere ultrastructure and stretch response in vertebrate muscle. It folds into numerous Ig and FnIII domains connected in tandem. Data on interdomain arrangements and dynamics are essential for understanding the function of this filament. Here, we report a mechanistic analysis of the conformational dynamics of two Ig domains from the N terminus of titin, Z1Z2, by using X-ray crystallography, SAXS, NMR relaxation data, and residual dipolar couplings in combination. Z1Z2 preferentially adopts semiextended conformations in solution, with close-hinge arrangements representing low-probability states. Although interdomain contacts are not observed, the linker appears to acquire moderate rigidity via small, local hydrophobic interactions. Thus, Z1Z2 constitutes an adaptable modular system with restricted dynamics. We speculate that its preexistent conformation contributes to the selective recruitment of the binding partner telethonin onto the repetitive surface of the filament. The structural interconversion of four Z1Z2 conformers is analyzed.

Connectin↗
PubMed1996

Differences in conformational dynamics of ribonucleases A and S as observed by infrared spectroscopy and hydrogen-deuterium exchange.

Differences in conformational dynamics of bovine pancreatic RNase A and RNase S have been investigated using hydrogen-deuterium (H-D) exchange in conjunction with Fourier transform infrared spectroscopy. Deuteration-induced spectral changes in the amide I and II regions were monitored as a function of time. Second-derivative analysis revealed similar amide I spectral patterns for both proteins in H2O as well as fully deuterated in D2O. However, the rate of amide proton exchange of RNase S is much faster than that of RNase A at 25 degrees C as determined by changes in the intensity ratio of amide II/amide I bands and frequency red-shifts of amide I components. The frequency red-shifts of the amide I components ascribed to beta-sheet, alpha-helix, and beta-turns are continuous as a function of time, indicating that both proteins are too small to contain isolated secondary structural groups containing only exchanged or unexchanged amide protons in the partially deuterated intermediate states. Despite the dramatic difference in H-D exchange rate, the patterns of spectral changes in the conformation-sensitive amide I regions of RNase A and RNase S are very similar throughout the course of deuteration, indicating a similar pathway of amide proton exchange in both proteins.

Animals↗
PubMed1999

Conformational dynamics of cytochrome c: correlation to hydrogen exchange.

We study the dynamical fluctuations of horse heart cytochrome c by molecular dynamics (MD) simulations in aqueous solution, at four temperatures: 300 K, 360 K, 430 K, and 550 K. Each simulation covers a production time of at least 1.5 nanoseconds (ns). The conformational dynamics of the system is analyzed in terms of collective motions that involve the whole protein, and local motions that involve the formation and breaking of intramolecular hydrogen bonds. The character of the MD trajectories can be described within the framework of rugged energy landscape dynamics. The MD trajectories sample multiple conformational minima, with basins in protein conformational space being sampled for a few hundred picoseconds. The trajectories of the system in configurational space can be described in terms of diffusion of a particle in real space with a waiting time distribution due to partial trapping in shallow minima. As a consequence of the hierarchical nature of the dynamics, the mean square displacement autocorrelation function, <|x(t) - x(0)|2>, exhibits a power law dependence on time, with an exponent of around 0.5 for times shorter than 100 ps, and an exponent of 1.75 for longer times. This power law behavior indicates that the system exhibits suppressed diffusion (sub-diffusion) in sampling of configurational space at time scales shorter than 100 ps, and enhanced (super-diffusion) at longer time scales. The multi-basin feature of the trajectories is present at all temperatures simulated. Structural changes associated with inter-basin displacements correspond to collective motions of the Omega loops and coiled regions and relative motions of the alpha-helices as rigid bodies. Similar motions may be involved in experimentally observed amide hydrogen exchange. However, some groups showing large correlated motions do not expose the amino hydrogens to the solvent. We show that large fluctuations are not necessarily correlated to hydrogen exchange. For example, regions of the proteins forming alpha helices and turns show significant fluctuations, but as rigid bodies, and the hydrogen bonds involved in the formation of these structures do not break in proportion to these fluctuations. Proteins 1999;36:175-191. Published 1999 Wiley-Liss, Inc.

Amides↗
PubMed2005

The role of calcium in the conformational dynamics and thermal stability of the D-galactose/D-glucose-binding protein from Escherichia coli.

We have characterized stability and conformational dynamics of the calcium depleted D-galactose/D-glucose-binding protein (GGBP) from Escherichia coli. The structural stability of the protein was investigated by steady state and time resolved fluorescence, and far-UV circular dichroism in the temperature range from 20 degrees C to 70 degrees C. We have found that the absence of the Ca(2+) ion results in a significant destabilization of the C-terminal domain of the protein. In particular, the melting temperature decreases by about 10 degrees C with the simultaneous loss of the melting cooperativity. Time resolved fluorescence quenching revealed significant loosening of the protein when highly shielded Trp residue(s) became accessible to acrylamide at higher temperatures. We have documented a significant stabilizing effect of glucose that mostly reverts the effect of calcium, that is, the thermal stability of the protein increases by about 10 degrees C and the melting cooperativity is restored. Moreover, the protein structure remains compact with low amplitude of the segmental mobility up to high temperatures. We have used molecular dynamics to identify the structural feature responsible for changes in the temperature stability. Disintegration of the Ca(2+)-binding loop seems to be responsible for the loss of the stability in the absence of calcium. The new insights on the structural properties and temperature stability of the calcium depleted GGBP contribute to better understanding of the protein function and constitute important information for the development of new biotechnological applications of this class of proteins.

Binding Sites↗