Fig. 8.
Summary of potential SynGAP missense mutation effects on the Ras/Rap-GTPase binding specificity and catalytic activity based on molecular modelling. The effects of key missense variants, including R401Q (Paul et al., 2025a) (Fig. 6C,F), R479Q (Figs. S15B,D and S16), E486K (Figs. S15B,D and S17), N487T (Pena et al., 2008) (Figs. 6B,E and S12), S604L (Fig. 5B,E), R596H (Figs. S13 and S14), and K628N (Fig. 5C,F), on the SynGAP–Ras/Rap-GTPase interactions are summarized to illustrate the dual activation mechanism. Arrows indicate missense mutation-induced changes relative to the WT systems across four metrics: SynGAP–GTPase binding affinity (FoldX-MD and Rosetta ), GTP binding affinity (MM/GBSA), GTP positional stability (RMSD of GTP heavy atoms), and catalytic-water coordination frequency. Upward arrows denote increased affinity, mobility, or water coordination, whereas downward arrows indicate decreases. Convergent effects are assigned when any of the evaluated metrics indicates an unfavorable change relative to WT; for example, any decrease in affinity or catalytic-water coordination results in a downward assignment for overall catalytic impact. The S604L missense mutation is estimated to not only decrease GTP binding but be disastrous for the Rap-GTPase GTP hydrolysis (see red X) due to its role in Switch II stabilization. Notably, experimental validation is essential for making any definitive determinations on any of these predicted effects of missense mutations on the GTPase binding or activity. For cross-reference, the full values and descriptions of the metrics used in the summary are provided in Table 1, Table 2, Table 3. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)