High-resolution FTIR spectroscopy of trisulfane HSSSH: a candidate for detecting parity violation in chiral molecules.

We report the first successful high-resolution analyses of the Fourier transform infrared (FTIR) spectrum of trisulfane. A band centered at 861.0292 cm-1 can be assigned unambiguously to the chiral trans conformer by means of ground state combination differences in comparison with known rotational spectra. A second band near 864.698 cm-1 is tentatively assigned to the cis conformer by comparison with theory. The results are discussed in relation to their importance for experimental attempts to measure the parity violating energy difference ΔpvE between the ground states of enantiomers of chiral molecules.

High resolution GHz and THz (FTIR) spectroscopy and theory of parity violation and tunneling for 1,2-dithiine (C4H4S2) as a candidate for measuring the parity violating energy difference between enantiomers of chiral molecules.

We report high resolution spectroscopic results of 1,2-dithiine-(1,2-dithia-3,5-cyclohexadiene, C4H4S2) in the gigahertz and terahertz spectroscopic ranges and exploratory theoretical calculations of parity violation and tunneling processes in view of a possible experimental determination of the parity violating energy difference ΔpvE in this chiral molecule. Theory predicts that the parity violating energy difference between the enantiomers in their ground state (ΔpvE ≃ 1.1 × 10(-11)(hc) cm(-1)) is in principle measurable as it is much larger than the calculated tunneling splitting for the symmetrical potential ΔE± < 10(-24) (hc) cm(-1). With a planar transition state for stereomutation at about 2500 cm(-1) tunneling splitting becomes appreciable above 2300 cm(-1). This makes levels of well-defined parity accessible to parity selection by the available powerful infrared lasers and thus useful for one of the existing experimental approaches towards molecular parity violation. The new GHz spectroscopy leads to greatly improved ground state rotational parameters for 1,2-dithiine. These are used as starting points for the first successful analyses of high resolution interferometric Fourier transform infrared (FTIR, THz) spectra of the fundamentals ν17 (1308.873 cm(-1) or 39.23903 THz), ν22 (623.094 cm(-1) or 18.67989 THz) and ν3 (1544.900 cm(-1) or 46.314937 THz) for which highly accurate spectroscopic parameters are reported. The results are discussed in relation to current efforts to measure ΔpvE.

Infrared laser induced population transfer and parity selection in (14)NH3: A proof of principle experiment towards detecting parity violation in chiral molecules.

We have set up an experiment for the efficient population transfer by a sequential two photon-absorption and stimulated emission-process in a molecular beam to prepare quantum states of well defined parity and their subsequent sensitive detection. This provides a proof of principle for an experiment which would allow for parity selection and measurement of the time evolution of parity in chiral molecules, resulting in a measurement of the parity violating energy difference ΔpvE between enantiomers of chiral molecules. Here, we present first results on a simple achiral molecule demonstrating efficient population transfer (about 80% on the average for each step) and unperturbed persistence of a selected excited parity level over flight times of about 1.3 ms in the beam. In agreement with model calculations with and without including nuclear hyperfine structure, efficient population transfer can be achieved by a rather simple implementation of the rapid adiabatic passage method of Reuss and coworkers and considering also the stimulated Raman adiabatic passage technique of Bergmann and coworkers as an alternative. The preparation step uses two powerful single mode continuous wave optical parametric oscillators of high frequency stability and accuracy. The detection uses a sensitive resonantly enhanced multiphoton ionization method after free flight lengths of up to 0.8 m in the molecular beam. Using this technique, we were able to also resolve the nuclear hyperfine structure in the rovibrational levels of the ν1 and ν3 fundamentals as well as the 2ν4 overtone of (14)NH3, for which no previous data with hyperfine resolution were available. We present our new results on the quadrupole coupling constants for the ν1, ν3, and 2ν4 levels in the context of previously known data for ν2 and its overtone, as well as ν4, and the ground state. Thus, now, (14)N quadrupole coupling constants for all fundamentals and some overtones of (14)NH3 are known and can be used for further theoretical analysis.

Survey of the high resolution infrared spectrum of methane ((12)CH4 and (13)CH4): partial vibrational assignment extended towards 12,000 cm(-1.).

We have recorded the complete infrared spectrum of methane (12)CH4 and its second most abundant isotopomer (13)CH4 extending from the fundamental range starting at 1000 cm(-1) up to the overtone region near 12,000 cm(-1) in the near infrared at the limit towards the visible range, at temperatures of about 80 K and also at 298 K with Doppler limited resolution in the gas phase by means of interferometric Fourier transform spectroscopy using the Bruker IFS 125 HR prototype (ZP 2001) of the ETH Zürich laboratory. This provides the so far most complete data set on methane spectra in this range at high resolution. In the present work we report in particular those results, where the partial rovibrational analysis allows for the direct assignment of pure (J = 0) vibrational levels including high excitation. These results substantially extend the accurate knowledge of vibrational band centers to higher energies and provide a benchmark for both the comparison with theoretical results on the one hand and atmospheric spectroscopy on the other hand. We also present a simple effective Hamiltonian analysis, which is discussed in terms of vibrational level assignments and (13)C isotope effects.

High resolution spectroscopy and the first global analysis of the Tetradecad region of methane 12CH4.

We present the first detailed analysis of the infrared spectrum of methane (12)CH4 in the so-called Tetradecad region from 2.1 to 1.6 µm (4760-6250 cm(-1)). New experimental high resolution FTIR spectra at 78 K and at room temperature combined with improved theoretical modeling have allowed quantum assignments to be greatly extended in this region. A global fit of all assigned lines of (12)CH4 in the 0-6200 cm(-1) region has been performed. In the end, 3012 line positions and 1387 intensities of 45 individual subbands of the Tetradecad were modeled up to J = 14. The root mean square deviations were 0.023 cm(-1) for line positions and 13.86% for line intensities in the Tetradecad region itself. Although this analysis is still preliminary, it is already sufficient to characterize the stronger bands throughout the whole of the Tetradecad. The calculated integrated intensity of the polyad is 1.399 × 10(-19) cm(-1)/(molecule cm(-2)) at 296 K. A "definitive" theoretical modeling of this spectral region of methane requires further work, but the present success substantially improves our understanding of methane spectroscopy as needed to interpret planetary atmospheres. Lines pertaining to three-fourths of the 60 sub-vibrational bands in this polyad have been assigned.

Panmixia in Zoarces viviparus: implications for environmental monitoring studies.

In this study, the genetic population structure of the eelpout Zoarces viviparus was investigated by using microsatellites. Samples were collected at 10 sites in the Baltic Sea, covering a distance of c. 90 km. Ten newly developed microsatellite loci were used to infer the population structure. No global spatial genetic differentiation was found (global F(ST) = 0·0001; D(est) = -0·0003), indicating strong gene flow at this scale, nor any clear pattern of isolation by distance. The results suggest that gene flow among the studied populations of Z. viviparus is stronger than usually thought, which might be caused by environmental homogeneity. This is important for planning and evaluating monitoring activities in this species and for the interpretation of ecotoxicological studies. Strong migration might lead to wrong conclusions concerning the pollution in a given area. Therefore, reference stations should be placed at a larger distance than presently practiced.

Assessing noise sources at synchrotron infrared ports.

Today, the vast majority of electron storage rings delivering synchrotron radiation for general user operation offer a dedicated infrared port. There is growing interest expressed by various scientific communities to exploit the mid-IR emission in microspectroscopy, as well as the far infrared (also called THz) range for spectroscopy. Compared with a thermal (laboratory-based source), IR synchrotron radiation sources offer enhanced brilliance of about two to three orders of magnitude in the mid-IR energy range, and enhanced flux and brilliance in the far-IR energy range. Synchrotron radiation also has a unique combination of a broad wavelength band together with a well defined time structure. Thermal sources (globar, mercury filament) have excellent stability. Because the sampling rate of a typical IR Fourier-transform spectroscopy experiment is in the kHz range (depending on the bandwidth of the detector), instabilities of various origins present in synchrotron radiation sources play a crucial role. Noise recordings at two different IR ports located at the Swiss Light Source and SOLEIL (France), under conditions relevant to real experiments, are discussed. The lowest electron beam fluctuations detectable in IR spectra have been quantified and are shown to be much smaller than what is routinely recorded by beam-position monitors.

High-resolution near infrared spectroscopy and vibrational dynamics of dideuteromethane (CH2D2).

We report the infrared spectrum of CH(2)D(2) measured in the range from 2800 to 6600 cm(-1) with the Zurich high-resolution Fourier transform interferometer Bruker IFS 125 prototype (ZP 2001, with instrumental bandwidth less than 10(-3) cm(-1)) at 78 K in a collisional enclosive flow cooling cell used in the static mode. Precise experimental values (with uncertainties between 0.0001 and 0.001 cm(-1)) were obtained for the band centers by specific assignment of transitions to the J = 0 level of 71 vibrational levels. In combination with 22 previously known band centers, these new results were used as the initial information for the determination of the harmonic frequencies, force constant parameters F(ij), anharmonic coefficients, and vibrational resonance interaction parameters. A set of 47 fitted parameters for an effective Hamiltonian reproduces the vibrational level structure of the CH(2)D(2) molecule up to 6600 cm(-1) with a root-mean-square deviation d(rms) = 0.67 cm(-1). The results are discussed in relation to the multidimensional potential hypersurface of methane and its vibrational dynamics.

High resolution Fourier transform spectroscopy of CH2D2 in the region 2350-2650 cm(-1): the bands nu5 + nu7, 2nu9, nu3 + nu4, nu3 + nu7 and nu5 + nu9.

The IR spectrum of the CH2D2 molecule has been measured in the region of 2350-2650 cm(-1) on a Bomem DA002 Fourier transform spectrometer with a resolution of 0.004 cm(-1) (FWHM, apodized) and analyzed with a Hamiltonian model which takes into account resonance interactions between all vibrational states in that region. More than 3000 transitions have been assigned to the bands 2nu9, nu3 + nu4, nu5 + nu9, nu5 + nu7 and nu3 + nu7 using ground state combination differences from the known ground state parameters. A set of 115 spectroscopic parameters for the excited vibrational states is obtained from a least squares adjustment. This reproduces the 646 initial upper ro-vibrational energies used in the fit with a d(rms) = 0.0036 cm(-1).

Molecular chirality and the fundamental symmetries of physics: influence of parity violation on rovibrational frequencies and thermodynamic properties.

We introduce the topic of fundamental symmetries of physics in relation to molecular chirality by a brief review of the development and current status of the theory of parity violation in chiral molecules. We then discuss in some detail CHBrClF (bromochlorofluoromethane) as a test case, to which the work of André Collet has contributed importantly. For this molecule and its isotopomers, we report here the first detailed theoretical calculations of the influence of parity violation on statistical thermodynamic properties. High-quality ab initio calculations (RPA, random phase approximation, and CASSCF, complete-active-space self-consistent-field) were performed to determine the small energy difference between R- and S-enantiomers of H and D isotopomers of bromochlorofluoromethane (CHBrClF, CDBrClF), and fluorooxirane ((1)H(3)C(2)OF) introduced by the parity-violating weak interaction. Together with vibrational and rotational frequency shifts caused by parity violation, these were used to determine the statistical thermodynamic quantities from the corresponding partition functions within the separable harmonic and in part also anharmonic adiabatic approximation. Temperature-dependent equilibrium constants for the stereomutation were calculated and are discussed in relation to biochemical homochirality.

Single thyroid hormone receptor monomers are competent for co-activator-mediated transactivation.

Thyroid hormone receptor (T(3)R) belongs to the superfamily of nuclear receptors containing highly related transcription factors that transform an incoming signal in the form of a lipophilic hormone into an activation of the basal transcriptional machinery. Like many other nuclear receptors, T(3)R acts preferentially as a heterodimer with retinoid X receptor (RXR) but it also has the unique property of binding as a monomer to DNA. This study demonstrates that T(3)R monomers bind preferentially to AGGTCA binding motifs and are able to co-exist with T(3)R-RXR heterodimers in the presence of limiting amounts of RXR. DNA-bound T(3)R monomers efficiently contact all three members of the p160 co-activator family, which in turn boost T(3)R monomer-mediated transactivation. In solution T(3)R monomers take only one agonistic conformation (c2(LPD)), whereas bound to DNA they also stabilize, like T(3)R-RXR heterodimers, a second agonistic conformation (c1(LPD)). Conformation c2(LPD) seems to be of lower ligand sensitivity (10 nM), whereas, both in T(3)R-RXR heterodimers and in DNA-bound T(3)R monomers, c1(LPD) is already activated at a ligand concentration of 1 nM. Taken together, these results suggest that single T(3)R monomers are fully competent for ligand-induced transactivation and that their role in gene regulation by thyroid hormone might have been underestimated.

Interaction of two novel 14-epivitamin D3 analogs with vitamin D3 receptor-retinoid X receptor heterodimers on vitamin D3 responsive elements.

This study provides a detailed and exact evaluation of the interactions between vitamin D3 receptor (VDR), retinoid X receptor (RXR), and vitamin D3 responsive elements (VDREs) mediated by two novel 14-epianalogs of 1,25-dihydroxyvitamin D [1,25(OH)2D3], 19-nor-14-epi-23-yne-1,25(OH)2D3 (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25(OH)2D3 (TX 527). Both analogs were more potent (14- and 75-fold, respectively) than 1,25(OH)2D3 in inhibiting cell proliferation and inducing cell differentiation. However, DNA-independent experiments indicated that both analogs had a lower affinity to VDR and that the stability of the induced VDR conformation, as measured by limited protease digestion assays, was similar (TX 527) or even weaker (TX 522) than that induced by the parent compound. However, DNA-dependent assays such as gel shift experiments revealed that those analogs were slightly more potent (3-7 times) than 1,25(OH)2D3 in enhancing binding of VDR-RXR heterodimers to a direct repeat spaced by three nucleotides (DR3) type VDRE. The functional consequences of the ligand-VDR-RXR-VDRE interactions observed in vitro were subsequently evaluated in transfection experiments. Both 14-epianalogs enhanced transcription of VDRE containing reporter constructs more efficiently than 1,25(OH)2D3 in COS-1 and MCF-7 cells regardless of the presence of ketoconazole. Transactivation activity is suggested to be a cell-specific process because maximal transcriptional induction and the half-maximal transactivation concentration for each reporter construct were different in both cell lines. The superagonistic transactivation activity closely resembled the biological potency of these analogs on the inhibition of MCF-7 cell proliferation. These data clearly indicate that superagonistic activity starts beyond the binding of the ligand-heterodimer (VDR-RXR) complex to VDRE and thus probably involves coactivator/corepressor molecules.

Central role of VDR conformations for understanding selective actions of vitamin D(3) analogues.

The vitamin D(3) receptor (VDR) acts primarily as a heterodimer with the retinoid X receptor (RXR) on different types of 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) response elements (VDREs). Therefore, DNA-bound VDR-RXR heterodimers can be considered as the molecular switches of 1alpha,25(OH)(2)D(3) signalling. Functional conformations of the VDR within these molecular switches appear to be of central importance for describing the biologic actions of 1alpha,25(OH)(2)D(3) and its analogues. Moreover, VDR conformations provide a molecular basis for understanding the potential selective profile of VDR agonists, which is critical for a therapeutic application. This review discusses VDR conformations and their selective stabilization by 1alpha,25(OH)(2)D(3) and its analogues, such as EB1089 and Gemini, as a monomer in solution or as a heterodimer with RXR bound to different VDREs and complexed with coactivator or corepressor proteins.

Diode-Laser Jet Spectra and Analysis of the nu(1) and nu(4) Fundamentals of CCl(3)F.

High-resolution infrared spectra have been measured for mixtures of CCl(3)F in Ne, expanded in a supersonic planar jet. We present the first analysis for the nu(4) fundamental and a complete analysis for the nu(1) band. Accurate spectroscopic constants have been obtained for both the nu(1) fundamental of the most abundant isotopic species, C(35)Cl(3)F, C(35)Cl(2)(37)ClF, and C(35)Cl(37)Cl(2)F. With respect to an earlier work [M. Snels, A. Beil, H. Hollenstein, M. Quack, U. Schmidt, and F. D'Amato, J. Chem. Phys. 103, 8846-8853 (1995)], the observation of Q branches of the three most abundant isotopomers allowed for an unambiguous determination of the nu(1) band origins. The nu(4) fundamental has not been the subject of a high-resolution analysis up to now. The observation of high-resolution spectra of the central part of the band permitted the determination of band origin, rotational constants, and Coriolis constant for the symmetric-top species, C(35)Cl(3)F. Copyright 2001 Academic Press.

Influence of parity violating weak nuclear potentials on vibrational and rotational frequencies in chiral molecules

We study the effect of parity violation on the vibrational and rotational frequencies of CHBrClF. We report the parity violating potentials as a function of reduced normal coordinates for all nine internal vibrational modes omega(1) to omega(9), using our new, accurate multiconfigurational-linear response (RPA and complete-active-space self-consistent field) approach. All modes omega(i) show a strongly mode dependent relative shift Delta(pv)omega(i)/omega(i) (between 0.08x10(-16) and 13.3x10(-16), much smaller than all previous experimental tests could detect, including the most recent ones). The results are discussed in relation to other tests of parity violation.

Response element and coactivator-mediated conformational change of the vitamin D(3) receptor permits sensitive interaction with agonists.

The vitamin D receptor (VDR) is the nuclear receptor for 1, 25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] that acts as a ligand-dependent transcription factor via combined contact with coactivator proteins (steroid receptor coactivator-1, transcriptional intermediary factor 2, and receptor associated coactivator 3) and specific DNA binding sites [vitamin D response elements (VDREs)]. Ligand-mediated conformational changes of the VDR contribute to the key mechanisms in this nuclear hormone signaling process. 1alpha,25(OH)(2)D(3), MC1288 [20-epi-1alpha,25(OH)(2)D(3)], ZK161422 [20-methyl-1alpha,25(OH)(2)D(3)], and Ro27-2310 (also called Gemini, having two side chains at carbon 20) were used as model VDR agonists. The analysis of agonist-induced VDR conformations and coactivator interactions were found to be insufficient for extrapolating in vivo activities. In DNA-independent assays, such as classical limited protease digestions and glutathione S-transferase pull downs, Gemini seemed to be up to 10,000-fold and the other VDR agonists 10- to 100-fold weaker than in functional in vivo assays. A more accurate description of the gene regulatory potential of VDR agonists was obtained with all tested VDR agonists by analyzing VDR conformations in the context of VDRE-bound VDR-retinoid X receptor heterodimers, in such assays as gel supershift, gel shift clipping, and limited protease digestion in the presence of DNA and cofactor. Coactivators were found to shift the ligand sensitivity (by a factor of 4 for Gemini) and the ratio of VDR conformations in the presence of DNA toward the high-affinity ligand binding conformation (c1(LPD)). In conclusion, the induction of response element- and coactivator-modulated VDR conformations appears to be a key step for the gene regulatory function of a VDR agonist. The quantification of these effects would be of central importance for the evaluation of the cell-specific efficacy of systemically applied 1alpha, 25(OH)(2)D(3) analogs.

Ligand-triggered stabilization of vitamin D receptor/retinoid X receptor heterodimer conformations on DR4-type response elements.

Nuclear receptors integrate an incoming signal in the form of a nuclear hormone by undergoing a conformational change that results via co-activator proteins in an activation of the basal transcriptional machinery. The vitamin D(3) receptor is the nuclear receptor for 1alpha,25-dihydroxyvitamin D(3 )(1alpha,25(OH)(2)D(3)) and is known to function as a heterodimer with the retinoid X receptor on DR3-type 1alpha,25(OH)(2)D(3) response elements. Here, it could be demonstrated that DR4-type response elements are at least as effective as DR3-type 1alpha,25(OH)(2)D(3) response elements. Gel shift clipping analysis showed that vitamin D(3) receptor-retinoid X receptor heterodimers form in response to 1alpha, 25(OH)(2)D(3) and retinoid X receptor ligands, the pan-agonist 9-cis retinoic acid (9cRA) and the retinoid X receptor-selective retinoid CD2425, different conformations on the DR4-type element of the rat Pit-1 gene. Interestingly, on this response element the heterodimeric complexes of retinoid X receptor with the thyroid hormone receptor, the retinoic acid receptor and the benzoate ester receptor also displayed characteristic individual ligand-dependent complex formation. On the level of complex formation, utilizing DNA affinity and functional assays, only vitamin D(3) receptor-retinoid X receptor heterodimers showed a synergistic interaction of both ligands. However, the sensitivity of vitamin D(3) receptor-retinoid X receptor heterodimers to 1alpha,25(OH)(2)D(3) was found to be much higher than to retinoid X receptor ligands. Taken together, this study demonstrates a unique interaction potential of vitamin D(3) receptor and retinoid X receptor but also establishes DR4-type response elements as multi-functional DNA binding sites with a potential to integrate various hormone signalling pathways.

The impact of functional vitamin D(3) receptor conformations on DNA-dependent vitamin D(3) signaling.

The vitamin D(3) receptor (VDR) is the nuclear receptor for 1alpha, 25-dihydroxyvitamin D(3) (VD) that acts primarily as a heterodimer with the retinoid X receptor (RXR) on different types of VD response elements, i.e., DNA-bound VDR-RXR heterodimers are the molecular switches in nuclear VD signaling pathways. In this study, DNA-dependent limited protease digestion assays and gel shift clipping assays were used for the analysis of VDR conformations and showed the same high ligand sensitivity for VD response element-bound VDR-RXR heterodimers (EC(50) of 0.1 nM for VD). In contrast, DNA-independent limited protease digestion assays clearly demonstrated a reduced ligand sensitivity for monomeric VDR in solution. Interestingly, the relative amount of reduction was found to be specific for each VDR agonist. Moreover, complex formation of the VDR on DNA resulted in a shift from the receptor's low-affinity ligand binding conformation (c3(LPD)) to its high affinity conformation (c1(LPD)). Finally, the characterization of the conformations of N- and C-terminally truncated VDR proteins defined the high-affinity ligand binding domain of the VDR as being positioned between amino acids 128 and 427. Taken together, the analysis of VDR conformations in solution in comparison to those of DNA-complexed VDR-RXR heterodimers allows a differentiation to be drawn between DNA-dependent and DNA-independent VD signaling pathways that can in turn be used for the identification of pathway selective VDR agonists.

Electroweak quantum chemistry of alanine: parity violation in gas and condensed phases.

Just how different are the energies of left- and right-handed alanine enantiomers because of parity violation? Substantial advances in electroweak quantum chemistry have provided new answers to this question. The present, advanced calculations lead to the conclusion that numerous previous claims of L-alanine stabilization by parity violation are unjustified. This introduces some extra pepper into current discussions of the origin of biomolecular homochirality. The picture shows a zwitterionic model with conformational changes and solvent effects, as included in the calculations.

Selective recognition of vitamin D receptor conformations mediates promoter selectivity of vitamin D analogs.

The transcription factor VDR is the nuclear receptor for 1alpha, 25-dihydroxyvitamin D3 (VD) and the mediator of all genomic actions of the nuclear hormone and its synthetic analogs. The sharp biological profile of the model VD analog 1(S), 3(R)-dihydroxy-20(R)-(5'-ethyl-5'-hydroxy-hepta-1'(E), 3'(E)-dien-1'-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (EB1089) (i.e., its high antiproliferative effect combined with low calcemic actions) has been correlated with the selectivity of EB1089 to activate heterodimeric complexes of VDR with its partner retinoid X receptor (RXR) on VD response elements (VDREs). These VDREs are formed by an inverted palindromic arrangement of two hexameric core binding motifs spaced by nine nucleotides (IP9) rather than VDREs that are formed by direct repeats with three intervening nucleotides (DR3). In this report, ligand-dependent gel-shift assays were used for a comparison of the ability of VD and EB1089 to stabilize VDR-RXR heterodimers on these two VDRE types. The gel-shift assays revealed EB1089 to be more sensitive for complexes on IP9-type VDREs than on DR3-type VDREs. In addition, a gel-shift clipping method was established to identify and compare complexes of ligand-stabilized VDR-RXR heterodimers on different VDREs. On each VDRE, two complexes could be discriminated that seemed to contain different functional conformations of the VDR and allowed a more differential view on DNA-complexed VDR-RXR heterodimers. The VDR-RXR conformation (which was more ligand-sensitive) gained through EB1089 a higher affinity (7-fold) for DNA binding and a more sensitive (9-fold) activation of an IP9-type VDRE than of a DR3-type VDRE, whereas with the natural hormone VD, no VDRE-type preference could be observed. This indicates that promoter selectivity of VDR ligands is based on their property to selectively increase affinity for VDREs and very sensitively stabilize VDR conformations in VDR-RXR-VDRE complexes.