Rapid protein-ligand costructures using chemical shift perturbations

Structure-based drug discovery requires the iterative determination of protein-ligand costructures in order to improve the binding affinity and selectivity of potential drug candidates. In general, X-ray and NMR structure determination methods are time consuming and are typically the limiting factor in the drug discovery process. The application of molecular docking simulations to filter and evaluate drug candidates has become a common method to improve the throughput and efficiency of structure-based drug design. Unfortunately, molecular docking methods suffer from common problems that include ambiguous ligand conformers or failure to predict the correct docked structure. A rapid approach to determine accurate protein-ligand costructures is described based on NMR chemical shift perturbation (CSP) data routinely obtained using 2D 1H-15N HSQC spectra in high-throughput ligand affinity screens. The CSP data is used to both guide and filter AutoDock calculations using our AutoDockFilter program. This method is demonstrated for 19 distinct protein-ligand complexes where the docked conformers exhibited an average rmsd of 1.17 +/- 0.74 A relative to the original X-ray structures for the protein-ligand complexes.     

Synthesis of Calcium(II) Amidinate Precursors for Atomic Layer Deposition through a Redox Reaction between Calcium and Amidines

We have prepared two new Ca^II amidinates, which comprise a new class of ALD precursors. The syntheses proceed by a direct reaction between Ca metal and the amidine ligands in the presence of ammonia. Bis(N,N′‐diisopropylformamidinato)calcium(II) ( 1 ) and bis(N,N′‐diisopropylacetamidinato)calcium(II) ( 2 ) adopt dimeric structures in solution and in the solid state. X‐ray crystallography revealed asymmetry in one of the bridging ligands to afford the structure [(η²‐L)Ca(μ‐η²:η²‐L)(μ‐η²:η¹‐L)Ca(η²‐L)]. These amidinate complexes showed unprecedentedly high volatility as compared to the widely employed and commercially available Ca^II precursor, [Ca₃(tmhd)₆]. In CaS ALD with 1 and H₂S, the ALD window was approximately two times wider and lower in temperature by about 150 °C than previously reported with [Ca₃(tmhd)₆] and H₂S. Complexes 1 and 2 , with their excellent volatility and thermal stability (up to at least 350 °C), are the first homoleptic Ca^II amidinates suitable for use as ALD precursors.     

Recreational runners with patellofemoral pain exhibit elevated patella water content

Increased bone water content resulting from repetitive patellofemoral joint overloading has been suggested to be a possible mechanism underlying patellofemoral pain (PFP). To date, it remains unknown whether persons with PFP exhibit elevated bone water content. The purpose of this study was to determine whether recreational runners with PFP exhibit elevated patella water content when compared to pain-free controls. Ten female recreational runners with a diagnosis of PFP (22 to 39 years of age) and 10 gender, age, weight, height, and activity matched controls underwent chemical-shift-encoded water-fat magnetic resonance imaging (MRI) to quantify patella water content (i.e., water-signal fraction). Differences in bone water content of the total patella, lateral aspect of the patella, and medial aspect of the patella were compared between groups using independent t tests. Compared with the control group, the PFP group demonstrated significantly greater total patella bone water content (15.4 ± 3.5% vs. 10.3 ± 2.1%; P = 0.001), lateral patella water content (17.2 ± 4.2% vs. 11.5 ± 2.5%; P = 0.002), and medial patella water content (13.2 ± 2.7% vs. 8.4 ± 2.3%; P < 0.001). The higher patella water content observed in female runners with PFP is suggestive of venous engorgement and elevated extracellular fluid. In turn, this may lead to an increase in intraosseous pressure and pain.     

Utilization of phosphinoamide ligands in homobimetallic fe and mn complexes: the effect of disparate coordination environments on metal-metal interactions and magnetic and redox properties

A series of homobimetallic phosphinoamide-bridged diiron and dimanganese complexes in which the two metals maintain different coordination environments have been synthesized. Systematic variation of the steric and electronic properties of the phosphinoamide phosphorus and nitrogen substituents leads to structurally different complexes. Reaction of [(i)PrNKPPh(2)] (1) with MCl(2) (M = Mn, Fe) affords the phosphinoamide-bridged bimetallic complexes [Mn((i)PrNPPh(2))(3)Mn((i)PrNPPh(2))] (3) and [Fe((i)PrNPPh(2))(3)Fe((i)PrNPPh(2))] (4). Complexes 3 and 4 are iso-structural, with one metal center preferentially binding to the three amide ligands in a trigonal planar arrangement while the second metal center is ligated by three phosphine donors. A fourth phosphinoamide ligand caps the tetrahedral coordination sphere of the phosphine-ligated metal center. M?ssbauer spectroscopy of complex 4 suggests that the metals in these complexes are best described as Fe(II) centers. In contrast, treatment of MnCl(2) or FeI(2) with [MesNKP(i)Pr(2)] (2) leads to the formation of the halide-bridged species [(THF)Mn(μ-Cl)(MesNP(i)Pr(2))(2)Mn(MesNP(i)Pr(2))] (5) and [(THF)Fe(μ-I)(MesNP(i)Pr(2))(2)FeI (7), respectively. Utilization of FeCl(2) in place of FeI(2), however, leads exclusively to the C(3)-symmetric complex [Fe(MesNP(i)Pr(2))(3)FeCl] (6), structurally similar to 4 but with a halide bound to the phosphine-ligated Fe center. The M?ssbauer spectrum of 6 is also consistent with high spin Fe(II) centers. Thus, in the case of the [(i)PrNPPh(2)](-) and [MesNP(i)Pr(2)](-) ligands, zwitterionic complexes with the two metals in disparate coordination environments are preferentially formed. In the case of the more electron-rich ligand [(i)PrNP(i)Pr(2)](-), complexes with a 2:1 mixed donor ligand arrangement, in which one of the ligand arms has reversed orientation relative to the previous examples, are formed exclusively when [(i)PrNLiP(i)Pr(2)] (generated in situ) is treated with MCl(2) (M = Mn, Fe): (THF)(3)LiCl[Mn(N(i)PrP(i)Pr(2))(2)(P(i)Pr(2)N(i)Pr)MnCl] (8) and [Fe(N(i)PrP(i)Pr(2))(2)(P(i)Pr(2)N(i)Pr)FeCl] (9). Bimetallic complexes 3-9 have been structurally characterized using X-ray crystallography, revealing Fe-Fe interatomic distances indicative of metal-metal bonding in complexes 6 and 9 (and perhaps 4, to a lesser extent). All of the complexes appear to adopt high spin electron configurations, and magnetic measurements indicate significant antiferromagnetic interactions in Mn(2) complexes 5 and 8 and no discernible magnetic superexchange in Fe(2) complex 4. The redox behavior of complexes 3-9 has also been investigated using cyclic voltammetry, and theoretical investigations (DFT) were performed to gain insight into the metal-metal interactions in these unique asymmetric complexes.     

Incorporating beta-turns and a turn mimetic out of context in loop 1 of the WW domain affords cooperatively folded beta-sheets.

To probe the conformational requirements of loop 1 in the Pin1 WW domain, the residues at the i + 2 and i + 3 positions of a beta-turn within this loop were replaced by dPro-Gly and Asn-Gly, which are known to prefer the conformations required at the i + 1 and i + 2 positions of type II' and type I' beta-turns. Conformational specificity or lack thereof was further examined by incorporating into the i + 2 and i + 3 positions a non-alpha-amino acid-based beta-turn mimetic (4-(2'-aminoethyl)-6-dibenzofuran propionic acid residue, 1), which was designed to replace the i + 1 and i + 2 positions of beta-turns. All these Pin WW variants are monomeric and folded as discerned by analytical ultracentrifugation, NMR, and CD. They exhibit cooperative two-state transitions and display thermodynamic stability within 0.5 kcal/mol of the wild-type WW domain, demonstrating that the acquisition of native structure and stability does not require a specific sequence and, by extension, conformation within loop 1. However, it could be that these loop 1 mutations alter the kinetics of antiparallel beta-sheet folding, which will be addressed by subsequent kinetic studies.     

Solid-Phase Synthesis and Encoding Strategies for Olefin Polymerization Catalyst Libraries

Active polymerization catalysts , novel resin-bound diimine complexes of nickel(II ) and palladium(II ) are obtained by combinatorial synthesis and combined in a catalyst library. By tagging with fluorescent markers, the catalysts can be coded. Therefore, after cleavage of the tag from the polymer-coated resin, HPLC can be used to determine the pathway along which the products were formed.     

Exploiting Incommensurate Symmetry Numbers: Rational Design and Assembly of M2M3′L6 Supramolecular Clusters with C3h Symmetry

Mixed-metal mesocates [M₂Pd₃Br₆L₆]⁴⁻ (M=Ti^IV, Sn^IV; L=4-diphenylphosphanyl-catecholate) have been synthesized, in which the two incommensurate symmetry elements generated by the different metal ions are linked by a rigid, bifunctional ligand to generate a C_3h-symmetrical cluster (see picture).     

Electrochemical behavior of layered annulenes

The cyclic voltammetric behavior of a series of dimeric [14] annulenes was examined and compared with the monomer. The data suggest a signigficant degree of interaction between the annulene rings when a three-carbon chain connects them, little or no interaction with an eight-carbon chain, and weak interaction with a four-carbon chain.     

The majority decision function for trees with 3 leaves

Kenneth May in 1952 proved a classical theorem characterizing simple majority rule for two alternatives. The present paper generalizes May’s theorem to the case of three alternatives, but where the voters’ preference relations are required to be trees with alternatives at the leaves. This paper with title “May’s Theorem for Trees” was presented at the joint DIMACS-LAMSADE workshop on Computer Science and Decision Theory, Université Paris-Dauphine, Paris 27–29 October 2004. It appeared in the proceedings Annales du LAMSADE 3 (2004), 259–266.