Small molecules complexation

Recently, several X-ray structures of the Src kinase have been determined with respect to a number of small-molecule complexes, including AP23464 and AP23451 [61] (Fig. 3), purvalanol and CPG77675 [62], and a des-methyl analog of STl-571 (imatinib) [63]. 

Zinc displays coordination numbers 4-6 in small-molecule complexes, and the coordination number 5 is particularly common (Cotton and Wilkinson, 1980). In aqueous solution zinc exists as the hexahydrate, Zn (OH2)e> although other zincate species may be observed under certain conditions [e.g., Zn ( OH)4 and Zn (OH2)2( OH)2 (see, e.g.,... 

Zinc may function to promote the nucleophilicity of a bound solvent molecule in both small-molecule and protein systems. The p/Ca of metal-free H2O is 15.7, and the p/Ca of hexaaquo-zinc, Zn (OH2)6. is about 10 (Woolley, 1975) (Table III). In a novel small-molecule complex the coordination of H2O to a four-coordinate zinc ion reduces the to about 7 (Groves and Olson, 1985) (Fig. 2). This example is particularly noteworthy since it has a zinc-bound solvent molecule sterically constrained to attack a nearby amide carbonyl group as such, it provides a model for the carboxypeptidase A mechanism (see Section IV,B). To be sure, the zinc ligands play an important role in modulating the chemical function of the metal ion in biological systems and their mimics. 

Subsequent to CO2 association in the hydrophobic pocket, the chemistry of turnover requires the intimate participation of zinc. The role of zinc is to promote a water molecule as a potent nucleophile, and this is a role which the zinc of carbonic anhydrase II shares with the metal ion of the zinc proteases (discussed in the next section). In fact, the zinc of carbonic anhydrase II promotes the ionization of its bound water so that the active enzyme is in the zinc-hydroxide form (Coleman, 1967 Lindskog and Coleman, 1973 Silverman and Lindskog, 1988). Studies of small-molecule complexes yield effective models of the carbonic anhydrase active site which are catalytically active in zinc-hydroxide forms (Woolley, 1975). In addition to its role in promoting a nucleophilic water molecule, the zinc of carbonic anhydrase II is a classical electrophilic catalyst that is, it stabilizes the developing negative charge of the transition state and product bicarbonate anion. This role does not require the inner-sphere interaction of zinc with the substrate C=0 in a precatalytic complex. 

Molecular Complexes. These species are formed by noncovalent interactions between the substrate and ligand. Among the kinds of complexspecies included in this class are small molecule-small molecule complexes, small molecule-macromolecule species, ion-pairs, dimers and other self-associated species, and inclusion complexes in which one ofthe molecules, the host, forms or possesses a cavity into which it can admit a guest molecule. 

Edwards, T. E., and Sigurdsson, S. T. (2002). Electron paramagnetic resonance dynamic signatures of TAR RNA—Small molecule complexes provide insight into RNA structure and recognition. Biochemistry 41, 14843-14847. 

Perform molecular dynamics simulations and energy minimizations for the target protein-small molecule complex (2W1T-8-chloro-cAMP) using AMBER 11 (downloaded from http // www.ambermd.org/) simulation package. 

Lang PT, Brozell SR, Mukherjee S et al (2009) DOCK 6 combining techniques to model RNA-small molecule complexes. RNA 15 1219-1230. doi rna.1563609... 

An alternative approach to representing the metal center has been developed for zinc(II) centers and applied to the modeling of the interaction of natural substrates and inhibitors of the enzyme human carbonic anhydrase[105 392,3931. Structurally characterized four-, five- and six-coordinate small-molecule complexes of zinc(II) were analyzed to determine the distribution of bond lengths and angles about the zinc ion. A function was developed that was able to reproduce these structural features and was added to the program YETI[394), developed for modeling small molecule-metalloprotein interactions. 

Protein-Small Molecule Complexes. - In this section, we address the recognition of small organic molecules or short peptides. Binding constants... 

Several structures of small molecule complexes with acetylcholinesterase have been solved. They reveal a binding site next to the catalytic serine preferrentially occupied by a positively charged moiety next to a hydrophobic portion. The positively charged functional groups almost superimpose in front of a trj tophan residue at the bottom of the gorge [25-27]. 

The observations of Klotz and Loh-Ming (1954) on the binding of pyri-dine-2-azo-dimethylaniline to protein through a cation bridge indicate that a similar behavior of zinc occurs in mixed protein-small molecule complexes. They have measured the stability constants of the dye with cations bound to protein (pepsin and albumin) and free in solution. For Zn and Cu specifically ... 

F. -X, Bon and R. Van Rapenbusch, Comput. Chem., 13(14), 387 (1989). Choodraw an Interactive Molecular Graphics Program (PC/XT/AT) to Display Small Molecules Complexed with Protein Fragments Selected from the Protein Data Bank. 

Up to now, most of our discussion featured small molecules, complexes, or clusters. In this section, we examine on how these conclusions could be extended to the realm of functional assemblies and nanomaterials. We begin with examining the structures and physical characteristics of carbon containing systems. We then progress to a discussion of organic nanotubes, metallic and encapsulated nanowires, and finally, nanodevices. 

The structural information available on the reduced state of Cu2Zu2 SOD provides a view of the copper site as a very flexible system, where the Cud) ion can shift between three- and four-coordination with a water molecule weakly interacting with it, giving rise to 4 -I- 1 coordination. The latter coordination is commonly observed in small molecule complexes [a recent example is provided by Lee et al. (S6)]. It is noteworthy to point out that a concerted movement of the metal and of some of the ligands seems responsible for the coordination changes observed in the reduced yeast SOD and bovine SOD structures. In the case of yeast SOD it appears that reduction of the copper ion occurs on C5n"stallization and that crystal packing does not play a role in the process. On the contrary, in the bovine SOD example, pH and the solution-like environment of one of the subunits seem to be responsible for the probable detachment of the His-61 from Cu(I). 

In light of recent advances in solid state Hg NMR, Raman, IR, EXAFS, and electronic spectrocopies summarized here, Hg(II) complexes can no longer be considered as spectroscopically silent. A formidable barrier to establishing reliable spectroscopic correlations with the coordination environment still exists because of the small number of well characterized small molecule complexes. Solution Hg NMR, vibrational, and electronic spectroscopies can distinguish complexes with a coordination number of 2 from those with CN = 3 or 4. None of these techniques can readily distinguish between three and four coordination however. Recent advances in solid-state Hg NMR spectroscopy unequivocally demonstrate that Hg-SR complexes with a primary coordination number of three or four can be readily distinguished. 

Useful energy + small molecules complex molecules... 

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