A molecular model of the folate binding site of Pneumocystis carinii dihydrofolate reductase

Summary The inhibition of Pneumocystis carinii dihydrofolate reductase (DHFR) continues to be the major treatment strategy for P. carinii pneumonia (PCP). The design of new anti-pneumocystis agents would be significantly enhanced by the availability of a 3D model of the methotrexate (MTX) binding site of the P. carinii DHFR. However, an X-ray crystal structure of the P. carinii DHFR is not yet available. Alignment of the amino acid sequences of P. carinii and Lactobacillus casei DHFRs indicates that the two proteins show approximately 80% homology among MTX binding-site residues. This high level of homology suggests that the L. casei DHFR MTX binding-site structure could serve as a structural template in developing a model of the P. carinii DHFR MTX binding site. Therefore, the X-ray crystal structure of L. casei DHFR was used to develop a 3D model of the methotrexate binding site of P. carinii DHFR. The molecular modeling and dynamics software QUANTA/CHARMm was used. Amino acid residue mutations and deletions were performed using QUANTA and macromolecular minimizations were achieved with CHARMm. The MTX binding-site residues of L. casei DHFR were mutated to the corresponding residues of the P. carinii DHFR sequence. The resulting structure was extensively minimized. The resulting P. carinii MTX binding-site model showed significant differences in hydrogen-bonding patterns from the L. casei MTX binding site. Also, the P. carinii site is more hydrophobic than the corresponding L. casei site. Analysis of atom-to-atom close contacts between methotrexate and protein binding-site residues indicates that the P. carinii MTX binding-site complex is primarily stabilized by hydrophobic interactions, while the L. casei complex is mostly stabilized by electrostatic interactions. The model is consistent with the observed increased sensitivity of P. carinii DHFR to lipid-soluble inhibitors and provides a rational basis for the design of new anti-pneumocystis agents.     

Measuring One Aspect of Teachers’ Affective States: Development of the Science Teachers’ Pedagogical Discontentment Scale

The aim of this research is to describe the development of the Science Teachers’ Pedagogical Discontentment Scale, an instrument that measures the discontentment that arises in teachers as they recognize a mismatch between their own pedagogical beliefs and goals and their actual classroom practices. From a conceptual change perspective, we explore the meaning of pedagogical discontentment and discuss its role in shaping teachers’ receptivity to messages of reform. We present an instrument that can be used to measure teachers’ pedagogical discontentment, an instrument that will allow science educators to better describe the affective states of teachers as they enter professional development experiences. The items for the initial instrument were derived from a series of interviews with practicing teachers; from these interviews, a group of 42 items were designed around a group of five subscales. The final instrument, revised after two rounds of field testing, includes 21 multiple‐choice items clustered around six subscales (subscales derived from interviews with science teachers). The processes used to develop the items and to refine instrument are discussed. Uses for this instrument to inform professional development experiences are explored as well as implications.     

WinDock: structure-based drug discovery on Windows-based PCs

In recent years, virtual database screening using high-throughput docking (HTD) has emerged as a very important tool and a well-established method for finding new lead compounds in the drug discovery process. With the advent of powerful personal computers (PCs), it is now plausible to perform HTD investigations on these inexpensive PCs. To make HTD more accessible to a broad community, we present here WinDock, an integrated application designed to help researchers perform structure-based drug discovery tasks under a uniform, user friendly graphical interface for Windows-based PCs. WinDock combines existing small molecule searchable three-dimensional (3D) libraries, homology modeling tools, and ligand-protein docking programs in a semi-automatic, interactive manner, which guides the user through the use of each integrated software component. WinDock is coded in C++.     

Crystal-to-Crystal Transformation of Magnets Based on Heptacyanomolybdate(III) Involving Dramatic Changes in Coordination Mode and Ordering Temperature

Two for one: Two unusual magnets based on the [Mo(CN)(7) ](4-) building block with Mn(II) linkers have been prepared with different topological 3D networks. Conversion of one into the other is triggered by dehydration during a single-crystal to single-crystal event (see picture; Mn:?dark red, Mo:?pink, C:?green, N:?blue, O:?red).     

Combined fit to BABAR and Belle Data on e^＋e^- →φπ^＋π^- and φf0（980）

A combined fit is performed to the BABAR and Belle measurements of the e^＋e^- →φπ^＋π^- and φf0（980） cross sections for center-of-mass energy between threshold and 3.0 GeV. The resonance parameters of the φ（1680） and Y（2175） are determined. The mass is （1681-12^＋10） MeV/c^2 and the width is （221-24^＋34） MeV/c^2 for the φ（1680）, and the mass is （2117-49^＋59） MeV/c^2 and the width is （164-80^＋69） MeV/c^2 for the Y（2175）. This information will shed light on the understanding of the nature of the excited φ and Y states observed in e＋e- annihilation.     

Dimensionality selection in a molecule-based magnet

Gaining control of the building blocks of magnetic materials and thereby achieving particular characteristics will make possible the design and growth of bespoke magnetic devices. While progress in the synthesis of molecular materials, and especially coordination polymers, represents a significant step towards this goal, the ability to tune the magnetic interactions within a particular framework remains in its infancy. Here we demonstrate a chemical method which achieves dimensionality selection via preferential inhibition of the magnetic exchange in an S=1/2 antiferromagnet along one crystal direction, switching the system from being quasi-two- to quasi-one-dimensional while effectively maintaining the nearest-neighbor coupling strength.     

Ag(nic)2 (nic = nicotinate): a spin-canted quasi-2D antiferromagnet composed of square-planar S = 1/2 Ag(II) ions

Square-planar S = 1/2 Ag(II) ions in polymeric Ag(nic)(2) are linked by bridging nic monoanions to yield 2D corrugated sheets. Long-range magnetic order occurs below T(N) = 11.8(2) K due to interlayer couplings that are estimated to be about 30 times weaker than the intralayer exchange interaction.     

Hydrogen bonding and multiphonon structure in copper pyrazine coordination polymers

We report a systematic investigation of the temperature-dependent infrared vibrational spectra of a family of chemically related coordination polymer magnets based upon bridging bifluoride (HF(2)-) and terminal fluoride (F-) ligands in copper pyrazine complexes including Cu(HF(2))(pyz)(2)BF(4), Cu(HF(2))(pyz)(2)ClO(4), and CuF(2)(H(2)O)(2)(pyz). We compare our results with several one- and two-dimensional prototype materials including Cu(pyz)(NO(3))(2) and Cu(pyz)(2)(ClO(4))(2). Unusual low-temperature hydrogen bonding, local structural transitions associated with stronger low-temperature hydrogen bonding, and striking multiphonon effects that derive from coupling of an infrared-active fundamental with strong Raman-active modes of the pyrazine building-block molecule are observed. On the basis of the spectroscopic evidence, these interactions are ubiquitous to this family of coordination polymers and may work to stabilize long-range magnetic ordering at low temperature. Similar interactions are likely to be present in other molecule-based magnets.