High Accuracy Prediction of PROTAC Complex Structures | JoVE Visualize

Area of Science:

Biochemistry
Structural Biology
Computational Chemistry

Background:

PROteolysis-TArgeting Chimeras (PROTACs) are heterobifunctional molecules that induce targeted protein degradation.
PROTACs function by forming a ternary complex between an E3 ligase, the target protein, and the PROTAC molecule.
Accurate structural modeling of these ternary complexes is crucial for understanding PROTAC mechanisms and designing new therapeutics.

Purpose of the Study:

To present a novel computational method for generating high-accuracy structural models of E3 ligase-PROTAC-target protein ternary complexes.
To validate the predictive accuracy of the developed computational method using known PROTAC structures and a blind test case.
To elucidate the relationship between ternary complex structure, stability, and PROTAC-mediated protein degradation.

Main Methods:

Development of a computational approach incorporating a "silent" convolution term into protein-protein docking to filter poses based on linker conformation.
Implementation of a clustering algorithm for models of multiple PROTACs targeting the same protein with the same E3 ligase.
Application of the method to known PROTAC structures and a blind test case involving BRAF mutant V600E.

Main Results:

The largest consensus clusters derived from the computational method consistently demonstrated high predictive accuracy for ternary complex structures.
The ensemble of predicted models accurately predicted the dissociation rate and cooperativity of ternary complexes.
The study confirmed that PROTACs stabilize favorable E3 ligase-target protein interactions, but not necessarily the most energetically favorable protein-protein geometry.

Conclusions:

The developed computational method enables accurate structural modeling of PROTAC ternary complexes, aiding in PROTAC design and optimization.
The findings highlight the importance of linker conformation and ternary complex stability in PROTAC efficacy.
This approach provides valuable insights into the mechanism of action of PROTACs and their potential as therapeutic agents.