Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement

The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.     

Nonadditive Interactions in Protein Folding: The Zipper Model of Cytochrome <Emphasis Type="Italic">c</Emphasis>

Hydrogen exchange experiments (Krishna et al. in J. Mol. Biol. 359:1410, 2006) reveal that folding–unfolding of cytochrome c occurs along a defined pathway in a sequential, stepwise manner. The simplified zipper-like model involving nonadditive coupling is proposed to describe the classical “on pathway” folding–unfolding behavior of cytochrome c. Using free energy factors extracted from HX experiments, the model can predict and explain cytochrome c behavior in spectroscopy studies looking at folding equilibria and kinetics. The implications of the proposed model are discussed for such problems as classical pathway vs. energy landscape conceptions, structure and function of a native fold, and interplay of secondary and tertiary interactions.     

Maize (Zea mays L.) seedling leaf nuclear proteome and differentially expressed proteins between a hybrid and its parental lines

To better understand the underlying molecular basis of leaf development in maize, a reference map of nuclear proteins in basal region of seedling leaf was established using a combination of 2DE and MALDI‐TOF‐MS. In total, 441 reproducible protein spots in nuclear proteome of maize leaf basal region were detected with silver staining in a pH range of 3–10, among which 203 spots corresponding to 163 different proteins were identified. As expected, proteins implicated in RNA and protein‐associated functions were overrepresented in nuclear proteome. Remarkably, a high percentage (10%) of proteins was identified to be involved in cell division and growth. In addition, comparative nuclear proteomic analysis in leaf basal region of highly heterotic hybrid Mo17/B73 and its parental lines was also performed and 52 of 445 (11.69%) detected protein spots were differentially expressed between the hybrid and its parental lines, among which 16 protein spots displayed nonadditively expressed pattern. These results indicated that hybridization between two parental lines can cause changes in the expression of a variety of nuclear proteins, which may be responsible for the observed leaf size heterosis.