Benchmarking Methods for PROTAC Ternary Complex Structure Prediction

Proteolysis targeting chimeras (PROTACs) are bifunctional
compounds
that recruit an E3 ligase to a target protein to induce ubiquitination
and degradation of the target. Rational optimization of PROTAC requires
a structural model of the ternary complex. In the absence of an experimental
structure, computational tools have emerged that attempt to predict
PROTAC ternary complexes. Here, we systematically benchmark three
commonly used tools: PRosettaC, MOE, and ICM. We find that these PROTAC-focused
methods produce an array of ternary complex structures, including
some that are observed experimentally, but also many that significantly
deviate from the crystal structure. Molecular dynamics simulations
show that PROTAC complexes may exist in a multiplicity of configurational
states and question the use of experimentally observed structures
as a reference for accurate predictions. The pioneering computational
tools benchmarked here highlight the promises and challenges in the
field and may be more valuable when guided by clear structural and
biophysical data. The benchmarking data set that we provide may also
be valuable for evaluating other and future computational tools for
ternary complex modeling.