Folding routes

P. E. Leopold, M. Montal and J. N. Onuchic. Protein folding funnels a kinetic approach to the sequence-structure relationship. Proceedings of the National Academy of Sciences, USA, 89 (1992), 8271 P G. Wolynes, J. N. Onuchic and D. Thirumalai. Navigating the folding routes. Science, 267 (1995), 1619 K. A. Dill and H. S. Chan. From Levinthal to pathways to funnels. Nature Structural Biology, 4 (1997), 10. 

This H (2009) Molecular gastronomy, a scientific look at cooking. Acc Chem Res 42 575-583 Wolynes PG, Onuchic JN, Thirumalai D (1995) Navigating the folding routes. Science... 

Figure C2.5.9. Examples of folding trajectories iT=T derived from the condition = 0.21. (a) Fast folding trajectory as monitored by y/t). It can be seen that sequence reaches the native state very rapidly in a two-state manner without being trapped in intennediates. The first passage time for this trajectory is 277 912 MCS. (b) Slow folding trajectory for the same sequence. The sequence becomes trapped in several intennediate states with large y en route to the native state. The first passage time is 11 442 793 MCS. Notice that the time scales in both panels are dramatically different.

The drug should be administered at three levels by the route proposed for humans. The high dose level should be set so as to have relevance in humans. For drugs that display significant toxic effects, this may be related to the maximally tolerated dose in the toxicity tests, for example, the dose causing less than 10% deviation in body weight versus controls. If there is little evidence of toxicity it may be more appropriate to base the dose level on a multiple (usually 25-fold) of the maximum therapeutic dosage recommended in humans. 

The major problem with the intravenous route in children is dosing errors. Because of the unavailability of stock solutions prepared for pediatric doses, errors in dilution of an adult stock solution have resulted in 10- to 20-fold errors in administered doses [87,88], A secondary problem is the maintenance of patent intravenous lines in infants and nonsedated children. 

If the paracellular route is perturbed to the extent that the pore radius R is changed from 12 A to 500 A, then F(5/500) 1.0 and Pparacell = 6.1 x 10 6 cm/sec. Although this represents a 12-fold gain from 5 X 10 7 cm/sec, the transcellular route taken by testosterone is yet the dominant pathway of the monolayer. In making the final calculations, we can conclude that the change in the observed / , will be imperceptible. 

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