Abstract
Despite the recent breakthrough of AlphaFold (AF) in the field of protein sequence-to-structure prediction, modeling protein interfaces and predicting protein complex structures remains challenging, especially when there is a significant conformational change in one or both binding partners. Prior studies have demonstrated that AF-multimer (AFm) can predict accurate protein complexes in only up to 43% of cases.1 In this work, we combine AlphaFold as a structural template generator with a physics-based replica exchange docking algorithm to better sample conformational changes. Using a curated collection of 254 available protein targets with both unbound and bound structures, we first demonstrate that AlphaFold confidence measures (pLDDT) can be repurposed for estimating protein flexibility and docking accuracy for multimers. We incorporate these metrics within our ReplicaDock 2.0 protocol2 to complete a robust in-silico pipeline for accurate protein complex structure prediction. AlphaRED (AlphaFold-initiated Replica Exchange Docking) successfully docks failed AF predictions including 97 failure cases in Docking Benchmark Set 5.5. AlphaRED generates CAPRI acceptable-quality or better predictions for 63% of benchmark targets. Further, on a subset of antigen-antibody targets, which is challenging for AFm (20% success rate), AlphaRED demonstrates a success rate of 43%. This new strategy demonstrates the success possible by integrating deep-learning based architectures trained on evolutionary information with physics-based enhanced sampling. The pipeline is available at github.com/Graylab/AlphaRED.
Competing Interest Statement
JJG is an unpaid board member (co-director) of the Rosetta Commons. Under institutional participation agreements between the University of Washington, acting on behalf of the Rosetta Commons, Johns Hopkins University may be entitled to a portion of revenue received on licensing Rosetta software including some methods described in this paper. JJG has a financial interest in Cyrus Biotechnology. Cyrus Biotechnology distributes the Rosetta software, which may include methods described in this paper. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies.
Footnotes
Figure 5 and Figure 8 revised. Results section updated to clarify on performance and success rates. More data included in Supplementary files.
