Computational crystallography initiative

Ernest Orlando Lawrence Berkeley National Laboratory, Computational Crystallography Initiative, http //cci.lbl.gov/. 

The initial coordinates r(0) are usually obtained from experimentally determined molecular structures, mainly from X-ray crystallography and NMR experiments. Alternatively, the initial coordinates can be based on computer models generated by a variety of modeling techniques (see Chapters 14 and 15). Note, however, that even the experimentally determined strucmres must often undergo some preparation steps before they can be used as initial structures in a dynamic simulation. 

There has been considerable and continuing investment in e-science and Grid-based computing around the world. Of particular interest for protein crystallography is the e-HTPX project funded by the UK research councils (http //www.e-htpx.ac.uk). The aim of e-HTPX is to unify the procedures of protein structure determination into a single all-encompassing interface from which users can initiate, plan, direct, and document their experiment either locally or remotely from a desktop computer. 

Aminoglycosides remain clinically important antibiotics. NMR provided the initial breakthrough in structural understanding of aminoglycoside action on the ribosome, and it remains a powerful tool for the biophysical characterization of drug-RNA interaction. The combined use of NMR, X-ray crystallography, thermodynamic and functional assays, and computational methods is needed to drive forward the development of new aminoglycosides with improved clinical properties. The rich data described above, combined with the application of new synthetic methods, bode well for the future. 

Normally, every GED paper reports the original intensities I(s) and sM(s) curve as recommended by the Commission on Electron Diffraction of the International Union of Crystallography [42]. Such an example fi om the electron diffraction study of dichlorodimethylsilane [43] is shown in Fig. 2. The experimental background shown in the upper part of Fig. 2 can be either hand-drawn or can be generated computationally using a series of polynomials satisfying a number of criteria. The initial background can be improved in the course of structure analysis [44]. 

DHFR catalyzes the reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F) using nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor (Fig. 17.1). Specifically, the pro-R hydride of NADPH is transferred stereospecifi-cally to the C6 of the pterin nucleus with concurrent protonation at the N5 position [1]. Structural studies of DHFR bound with substrates or substrate analogs have revealed the location and orientation of H2F, NADPH and the mechanistically important side chains [2]. Proper alignment of H2F and NADPH is crucial in enhancing the rate of the chemical step (hydride transfer). Ab initio, mixed quantum mechanical/molecular mechanical (QM/MM), and molecular dynamics computational studies have modeled the hydride transfer process and have deduced optimal geometries for the reaction [3-6]. The optimal C-C distance between the C4 of NADPH and C6 of H2F was calculated to be 2.7A [5, 6], which is significantly smaller than the initial distance of 3.34 A inferred from X-ray crystallography [2]. One proposed chemical mechanism involves a keto-enol tautomerization (Fig. 

For simulations of large biomolecules, it is necessary to have a reliable initial structure, obtained by X-ray crystallography, NMR spectroscopy,i22 or homology modeling using known structures believed to be similar to the one of interest. Enzymes are densely packed molecules with a well defined tertiary structure. Despite the size of these molecules, the relative rigidity of native enzymes results in limited conformational flexibility, rendering these systems amenable to computer simulation. 

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