Flip-flop model

If FC>FCa (perhaps indicating a dissolution-rate-limited absorption) the exact opposite will hold true. (Please see the discussion of the flip-flop model at the end of this chapter.)... 

These results indicate that is it possible to change the fold of a protein by changing a restricted set of residues. They also confirm the validity of the rules for stability of helical folds that have been obtained by analysis of experimentally determined protein structures. One obvious impliction of this work is that it might be possible, by just changing a few residues in Janus, to design a mutant that flip-flops between a helical and p sheet structures. Such a polypeptide would be a very interesting model system for prions and other amyloid proteins. 

Lipophilicity is intuitively felt to be a key parameter in predicting and interpreting permeability and thus the number of types of lipophilicity systems under study has grown enormously over the years to increase the chances of finding good mimics of biomembrane models. However, the relationship between lipophilicity descriptors and the membrane permeation process is not clear. Membrane permeation is due to two main components the partition rate constant between the lipid leaflet and the aqueous environment and the flip-flop rate constant between the two lipid leaflets in the bilayer [13]. Since the flip-flop is supposed to be rate limiting in the permeation process, permeation is determined by the partition coefficient between the lipid and the aqueous phase (which can easily be determined by log D) and the flip-flop rate constant, which may or may not depend on lipophilicity and if it does so depend, on which lipophilicity scale should it be based ... 

Figure 2.4 Flip-flop switch model of wake and slow wave sleep active systems. Mutually inhibitory connections exist between GABAergic/Galaninergic slow wave sleep active neurons in the ventrolateral preoptic area (VLPO) of the anterior hypothalamus and aminergic neurons in the hypothalamus (histamine (HA) neurons in the tuberomammillary nucleus (TMN)) and brainstem (serotonin (5-HT) neurons in the dorsal raphe (DR) and noradrenaline (NA) neurons in the locus coeruleus (LC)). Orexinergic neurons in the perifornical hypothalamus (PFH) stabilize the waking state via excitation of the waking side of the flip-flop switch (aminergic neurons).

The original proposal of the approach, supported by a Monte Carlo simulation study [36], has been further validated with both pre-clinical [38, 39] and clinical studies [40]. It has been shown to be robust and accurate, and is not highly dependent on the models used to fit the data. The method can give poor estimates of absorption or bioavailability in two sets of circumstances (i) when the compound shows nonlinear pharmacokinetics, which may happen when the plasma protein binding is nonlinear, or when the compound has cardiovascular activity that changes blood flow in a concentration-dependent manner or (ii) when the rate of absorption is slow, and hence flip-flop kinetics are observed, i.e., when the apparent terminal half-life is governed by the rate of drug input. 

In order to get this circuit to start, the UIC statement must be included in the. TRAN simulation. Flip-flops inside the model need the UIC directive in order to initialize properly. The SPICE engine has a difficult time determining the steady-state operating point of bistable circuit like the flip-flop without the UIC. Also, the ABSTOL OPTIONS parameter for current absolute current error tolerance has been changed from lp to 1/x to aid convergence. 

Quasar not only considers one conformer per molecule but also represents each molecule by an ensemble of conformers in different orientations and protonation states (called fourth dimension [21]), thereby reducing the bias associated with the choice of the bioactive conformation. The fifth dimension refers to the possibility to consider an ensemble of different induced-fit models [22] and the sixth dimension allows for the simulation of local induced H-bond flip-flop and various solvation effects [23]. 

How is a flip-flop inferred It depends on the modeling style being followed and the context under which a variable is assigned a value. This... 

Here is a model of an up-down counter that shows flip-flops being modeled. 

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