Gag-Pol Processing during HIV-1 Virion Maturation: A Systems Biology Approach
Figure 4
The effect of parameter variation on the virion maturation time (VMT).
(A) The effect of varying each parameter individually along a geometric series between 0.1 to 10 times its default value, while fixing all other parameters at their default values. Color symbols depict VMT as a function of the parameters with the strongest effects (kcat of CA/SP1: red; rate constant of Gag-Pol auto-cleavage: blue; KM of NC/SP2: green; KM (yellow) and kcat (brown) of p6pol/PR; kd of Gag-Pol: purple); the effect of variation in all other parameters is illustrated by black symbols, which are overlaid on the horizontal line positioned at default VMT, indicating no discernible effect. (B–C) Multivariate exploration of the parameter space. All parameters were drawn randomly from lognormal distributions parameterized such that 95% of the values fell in the range of 0.1 to 10 times the default value of the parameters, or 0.01 to 100 times the default for the parameters with no direct empirical estimates. Default parameter values are indicated by solid vertical lines, the limits of the 95% range by dashed vertical lines. The catalytic rate constant of CA/SP1 cleavage (B) had a strong impact on VMT; the rate constant of Gag-Pol auto-cleavage had very similar effect. None of the other parameters had any discernible effect on VMT: (C) shows a representative example with VMT plotted against the catalytic rate constant of NC/SP2 cleavage. Results from 10,000 simulations are shown; default VMT is indicated by solid horizontal line; parameters were plotted on a log scale in all three panels, with a dimension of s−1 in B–C.