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  • The differences between ground and transition state properti


    The differences between ground and transition state properties are exemplified by a comparison of our human–yeast results with those of a structural study of possible differences in ubiquitin-Uba-1 binding in yeast (known structure) with human (simulated in [12]). Their discussion focuses on Ubiquitin contacts with Tyr 571 (618 in our site numbering) in the CCD domain. According to Fig. 3 and its caption, there are substantial differences between yeast and human profiles here, and they are related to differences in tilts of the hydrophobic pivots. These are consistent with the modeling results, and also show the importance of allometric interactions between folded CC and CCD domains (Fig. 5). Human AAD adenylation (ATP) sites are 478, 504, 515, and 528. The overall BLAST identities and positives for yeast and human Uba1 are 52% and 71%, and these increase in the 400–600 ADD range to 63% and 80%. This range is shown in Fig. 6, and we see strong similarities in the two profiles. Their correlation is 86%, which means that is more effective in the 400–600 ADD range than even BLAST positives (80%) because it uses the MZ scale and because W* has been chosen to display level set hydrophobic adenylation domain pivots. From Fig. 6 we see that the four sites are concentrated in the center of the ADD structural domain. They line the amphiphilic range from the hydrophobic pivot at 478 to close to the apply for hinge at 535. The profile not only displays a stronger yeast–human ADD correlation than BLAST, but it also has revealed a hydropathic cascade of ATP binding sites. Among mammals the similarities are of course greater. The overall correlation of the mouse and human profiles is 97.2%, which increases in the 400–600 ADD range to 98.6 %. There has recently been some interest in Uba6, which is most similar to slime mold, with BLAST identities of 59% and positives 73% in the 400–600 ADD range. The 400–600 ADD correlation of the two profiles is a striking 87%, so functional differences probably arise outside the ADD binding domain. Human Uba6 and Uba1 have distinct preferences for E2 charging in vitro, and their specificity depends in part on their C-terminal ubiquitin-fold domains, which recruit E2s  [13]. Comparison of Uba1 of yeast and slime mold with Uba6 shows that for the most part, where Uba6 differs from one of the two, it is similar to the other. The exceptional region is UFD, the ubiquitin fold domain (Fig. 5), where Uba6 has a strong hydrophobic peak. Similar differences are obvious in the human and fruit fly profiles. This “only” confirms the main conclusion of [13], but note that it does so through a simple one-dimensional analysis that also includes many species’ versions of Uba1.
    Conclusions At present the most sophisticated structural studies involving MDS simulations with explicit water  [13] can reveal short-range interspecies differences in Uba-E1 — Ub binding, but long-range interactions are not identified. Proteins are near thermodynamic critical points in amino acid configuration space, and near such points (especially transition states), long-range and short-range interactions are balanced. In many proteins the short-range interactions evolve in subtle ways inaccessible to experiment, while here we have shown that the long-range interactions change in ways that can be easily recognized in . Evolutionary trends are easily recognized by thermodynamic scaling theory.
    Introduction Panax ginseng C.A. Mey (Arialaceae) has been used in health food and traditional herbal medicine for more than 1000years. It can prevent the risks of various cancers (Yun & Choi, 1995). It is known to be toxic (Chang, Seo, Gyllenhaal, & Block, 2003) but its effects on the cardiovascular, immune, renal, and central nervous systems are undefined (Gao et al., 2009, Gao et al., 2013, Wang et al., 2006, Xu et al., 2013). There is commercial interest in ginseng on the basis of its purported cancer prevention benefits (Wang et al., 2007, Yi et al., 2010). Ginsenosides from the plant genus Panax are a class of steroid glycosides and triterpene saponins. Ginsenosides and derivatives with less polar chemical structures possess higher cytotoxic activity towards cancer cells (Dong et al., 2011). Previous studies have demonstrated that Panax ginseng could prevent malignancy by inhibiting the 26S proteasome (Chang et al., 2008, Wong et al., 2010). However, there have been no studies on the effects of Panax ginseng on ubiquitin-activating enzyme (UAE or E1) in the ubiquitin activation of the ubiquitin–proteaosome system (UPP).