brainstorming G3PD2 (inhibitor case study) reasons for not fitting

[dczielinski]

G3PD2 has a generally pretty poor fit. Need to brainstorm ideas for why that might be.

Possibilities

1. solver issues (many parameters, a perfect fit does exist but the solver can't find it) - can try more trials
2. data inconsistency - overspecified parameters can't be fit perfectly inherently - can try the parameter sweeper or a hypercube data generator to account for uncertainty - maybe stumble on a point that works (this would rule out point 1)
3. issues with the simulated data - double check the equations used, though this was done carefully by resimulating plots

[dczielinski]

Since there are limited binding reactions that are supposed to correspond to a large number of different inhibition patterns, I think 2 is most likely. Going to be hard to sweep through parameters for consistent ones with so many data points though. At least I can calculate the final dissociation constants and compare them to the measured Ki values.

[dczielinski]

I guess we ideally would show that the inhibitor equations with the parameters plugged in are inconsistent. This inconsistency might actually result from having to assume that the cosubstrate is saturating, or from other interactions between saturation and inhibition by the same metabolite... Need to think about if we can prove or show this though, because showing inconsistency I think requires us to have an overall rate law, in which case I don't know if we could just plug in the measured values into it...

I'm actually kind of thinking that we should be able to make an overall rate law for this enzyme if we make Alberty's rapid equilibrium assumption for an ordered mechanism and add the inhibitors terms to that? Not sure if the fact that the inhibitor is also a substrate messes that up... Will explore that too

[dczielinski]

could be addressed by parameter scan or adding one data point at a time