prefers the "native" conformation, which is commonly observed in KRAS crystal structures (Figure ) . Interestingly, our simulations suggest that with LY3537982, for which water-bridged interactions to Gly10 are frequently observed (Figure ), the configuration of Thr58 is more flexible, promoting a "flipped" orientation of Thr58 (Figure ). This "flipped" Thr58 conformation is observed in the co-crystal structures of SII-P binders that displace the water in this location with a polar nitrile group; for instance, with adagrasib 7 .