Mutations in the KRAS protein are among the most common drivers of human cancers, including lung, pancreatic, and colorectal tumors. Despite decades of effort, KRAS has been considered a particularly difficult therapeutic target. A promising new strategy, known as targeted protein degradation (TPD), is beginning to overcome this challenge.
In TPD, small molecules called PROTACs (Proteolysis Targeting Chimeras) eliminate a disease-associated protein rather than simply inhibiting it. PROTACs are built with two binding components: one attaches to the protein of interest, while the other recruits an E3 ligase — a component of the cell’s protein recycling machinery. By bringing these two proteins into proximity, PROTACs promote ubiquitination and subsequent degradation of the disease-causing protein.
A central difficulty in designing PROTACs lies in identifying the productive protein–protein interactions (PPIs) between the target protein and the E3 ligase. These PPIs are often non-native, dynamic, and transient, making them challenging to predict.
To address this, we employed the computing resources of Folding@home, enabling ~1.5 milliseconds of all-atom molecular dynamics (MD) simulations of the KRAS protein with the von Hippel–Lindau (VHL) E3 ligase. From these simulations, we applied an advanced non-Markovian dynamic model — the Integrative Generalized Master Equation (IGME) — to characterize the conformational ensemble of the KRAS–VHL encounter complex.
Our analysis identified six metastable encounter states with distinct PPI interfaces. Three of these states demonstrated favorable geometries for PROTAC linker design, and notably, one state showed remarkable agreement with a recently determined crystal structure of a potent KRAS degrader.
These findings highlight how physics-based modeling can reveal otherwise hidden opportunities for degrader design. By uncovering the dynamic and metastable PPIs that underlie targeted protein degradation, we are advancing toward the rational design of new therapies against KRAS-driven cancers.
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