Solvent-dependent Conformational Changes Research Articles

Cyclic Peptide Design Guided by Residual Dipolar Couplings, J-Couplings, and Intramolecular Hydrogen Bond Analysis.

Cyclic peptides have long tantalized drug designers with their potential ability to combine the best attributes of antibodies and small molecules. An ideal cyclic peptide drug candidate would be able to recognize a protein surface like an antibody while achieving the oral bioavailability of a small molecule. It has been hypothesized that such cyclic peptides balance permeability and solubility using their solvent-dependent conformational flexibility. Herein we report a conformational deconvolution NMR methodology that combines residual dipolar couplings, J-couplings, and intramolecular hydrogen bond analysis along with conformational analysis using molecular dynamics simulations and density functional theory calculations for studying cyclic peptide conformations in both low-dielectric solvent (chloroform) and high-dielectric solvent (DMSO) to experimentally study the solvent-dependent conformational change hypothesis. Taken together, the combined experimental and computational approaches can illuminate conformational ensembles of cyclic peptides in solution and help identify design opportunities for better permeability.

Solvent-Dependent Conformational Change in Cephalosporin by HPLC Method

Solvent-Dependent Conformational Change in Cephalosporin by HPLC Method

Solvent-dependent conformational and fluorescence change of an N-phenylbenzohydroxamic acid derivative bearing two pyrene moieties

The conformation of N-phenylbenzohydroxamic acid has been reported to change depending on the solvent properties. Here, we newly synthesized N-phenylbenzohydroxamic acid derivative, which contains two pyrene moieties separated from the phenyl rings by ethylene linkers. It showed solvent-dependent conformational change, and its fluorescence was also solvent-dependent, that is, only monomer fluorescence of pyrene was observed in DMSO or DMF, whereas the excimer fluorescence was observed in CH2Cl2 or CHCl3. Thus, the structural characteristics could be converted to fluorescence change as output, which would be a good candidate as a fluorescent sensor.

Fast reactivity of a cyclic nitrone-calix[4]pyrrole conjugate with superoxide radical anion: theoretical and experimental studies.

Nitrone spin traps have been employed as probes for the identification of transient radical species in chemical and biological systems using electron paramagnetic resonance (EPR) spectroscopy and have exhibited pharmacological activity against oxidative-stress-mediated diseases. Since superoxide radical anion (O2(•-)) is a major precursor to most reactive oxygen species and calix[4]pyrroles have been shown to exhibit high affinity to anions, a cyclic nitrone conjugate of calix[4]pyrrole (CalixMPO) was designed, synthesized, and characterized. Computational studies at the PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) level suggest a pendant-type linkage between the calix[4]pyrrole and the nitrone to be the most efficient design for spin trapping of O2(•-), giving exoergic reaction enthalpies (ΔH(298K,aq)) and free energies (ΔG(298K,aq)) of -16.9 and -2.1 kcal/mol, respectively. (1)H NMR study revealed solvent-dependent conformational changes in CalixMPO leading to changes in the electronic properties of the nitronyl group upon H-bonding with the pyrrole groups as also confirmed by calculations. CalixMPO spin trapping of O2(•-) exhibited robust EPR spectra. Kinetic analysis of O2(•-) adduct formation and decay in polar aprotic solvents using UV-vis stopped-flow and EPR methods gave a larger trapping rate constant for CalixMPO and a longer half-life for its O2(•-) adduct compared to the commonly used nitrones. The unusually high reactivity of CalixMPO with O2(•-) was rationalized to be due to the synergy between the α-effect and electrostatic effect by the calix[4]pyrrole moiety on O2(•-) and the nitrone, respectively. This work demonstrates for the first time the application of an anion receptor for the detection of one of the most important radical intermediates in biological and chemical systems (i.e., O2(•-)).

Conformational change in the thiazole and oxazoline containing cyclic octapeptides, the patellamides. Part 2. Solvent dependent conformational changeElectronic supplementary information (ESI) available: further calculational details. See http://www.rsc.org/suppdata/p2/b2/b201824c/

Solvent dependent conformational change of the thiazole and oxazoline containing cyclic peptides, the patellamides, is examined by a combination of experimental and theoretical methods. A mechanism for the simultaneous formation of two type-II β-turns in the patellamides is proposed based on molecular dynamics and NOE restrained molecular dynamics studies as well as literature evidence. The effect of the solvent and desymmetrisation of the patellamides is crucial, with symmetrical patellamides in polar solvents giving the open type-I conformation, whereas symmetrical patellamides in non-polar solvents and asymmetrical patellamides in both polar and non-polar solvents give rise to the folded type-II conformation.

Folding of a β-cyclodextrin monosubstituted at its secondary face, revealed by NMR studies of local structural variations

The 1H NMR study of a CD mono-functionalized at its secondary face is presented. It is shown that mono-(3-Tyr-3-deoxy- altro)-β-CD undergoes a solvent-dependent conformational change. Passing from organic medium to water, a stable self-inclusion complex is formed. Such a folding is accompanied by a local structural modification of the substituted altrose ring, which can be easily detected from the important variation of its H1–H2 coupling constant.

Use of photoinduced energy-transfer to probe solvent-dependent conformational changes in a flexible Ru/Os dinuclear complex

Solvent-dependent conformational changes of a poly(oxoethylene) bridge linking [Ru(bipy)3]2+ and [Os(bipy)3]2+ units can be probed by measuring the extent of Ru→Os photoinduced energy transfer.

Relationship between electron transfer and the structure of a quinone-linked zinc porphyrin with a flexible peptide spacer

The solvent-dependent conformational change of the covalently linked porphyrin–peptide–quinone triad 1, as determined by 1H NMR and electronic absorption spectra, obviously reflects an intramolecular electron transfer reaction from the zinc porphyrin to quinone in both polar and nonpolar solvents.

Cystine peptides.

NHCH3 (X = Gly 1, Ala 2, Aib 3, Leu 4 and D‐Ala 5), have been investigated by Raman and circular dichroism (CD) spectroscopy. Solid state Raman spectra are consistent with β‐turn conformations in all five peptides. These peptides exhibit similar conformations of the disulfide segment in the solid state with a characteristic disulfide stretching frequency at 519 ± 3 cm‐1, indicative of a trans‐gauche‐gauche arrangement about the Cα—Cβ—S—S—Cβ—Cα bonds. The results correlate well with the solid state conformations determined by X‐ray diffraction for peptides 3 and 4. CD studies in chloroform and dimethylsulfoxide establish solvent dependent conformational changes for peptides 1, 3 and 5. Disulfide chirality has been derived using the quadrant rule. CD results together with previously reported nuclear magnetic resonance (n.m.r.) data suggest a conformational coupling between the peptide backbone and the disulfide segment.

Binding and hydrolysis of ATP by cardiac myosin subfragment 1: effect of solution parameters on transient kinetics.

Transient kinetic data of ATP binding and cleavage by cardiac myosin subfragment 1 (S1) were obtained by fluorescence stopped flow and analyzed by using computer modeling based on a consecutive, reversible two-step mechanism: (formula: see text) where M1 and M12 denote myosin species with enhanced fluorescence and K'O = K0/(K0[ATP] + 1). The kinetic constants K0, k12, k23, and k32 and the fractional contributions of M1 and M12 to the total fluorescence are analyzed over a range of systematically varied solution parameters. The initial ATP binding equilibrium (K0), which decreases with increasing pH, is facilitated by a positively charged protein residue with a pK of 7.1. An active-site charge of +1.5 is determined from the ionic strength dependence. The rate constants k12, k23, and k32 also exhibit pK's near neutrality but increase with increasing pH. The majority of the large (-54 kJ/mol) negative free energy of ATP binding occurs upon S1 isomerization, k12, and a large increase in entropy (183 J/kmol at 15 degrees C) is associated with the cleavage step. The equilibrium constant for the cleavage step, K2, is determined as 3.5 at pH 7.0, 15 degrees C, and 200 mM ionic strength. There are no significant changes in fractional contributions to total fluorescence enhancement due to solvent-dependent conformational changes of S1 in these data. When values for the combined rate constants are calculated and compared with those determined by graphical analysis, it is observed that graphical analysis overestimates the binding rate constant (K0k12) by 25% and the hydrolysis rate constant (k23 + k32) by as much as 30%.(ABSTRACT TRUNCATED AT 250 WORDS)

The conformations of adenosine mononculeotide in water and dimethylsulfoxide

Summary The conformation of adenosine-5′-monophosphate has been determined, using the lanthanide probe technique, in DMSO. The conformation found and the one previously found in aqueous solution are compared. The two differ by a large rotation of the base about the glycosidic linkage. The results help define in precise terms the nature of solvent dependent conformational changes for this molecule and the technique may be extended to many others.