Advancing Template-Based Flexible Docking of P450-Heme Complexes via JAX MD

AlphaFold2 has advanced protein structure prediction but often overlooks complexes with essential ligands, crucial for understanding protein-ligand interactions relevant to drug design. AlphaFill was developed to integrate ligands and ions from experimental structures into predicted models. However, many resulting complexes lack precise spatial constraints, leading to clashes between filled heme atoms and the P450 structure, as well as discrepancies in the key Fe-S bond.So, we propose FlexFill, a rapid flexible docking algorithm based on JAX MD. Specifically, FlexFill takes the predicted P450 structure as input to generate the P450-heme complex structure. During the docking process, we leverage JAX MD to account for the structural flexibility of P450. Unlike traditional molecular dynamics methods, we developed a customized energy function that focuses on the atoms near the pocket, significantly reducing runtime while satisfying spatial constraints.The results indicate that AlphaFill experienced almost 50% structural crashes, while FlexFill exhibited a substantially lower rate at less than 5%. Furthermore, FlexFill is 25% faster than AlphaFill, with further speed improvements by removing redundant entries from the template library. These observations suggest that FlexFill is capable of generating high-fidelity P450heme complexes and has the ability to flexibly dock a diverse array of protein-ligand complexes. Code and pre-trained model are released at https://github.com/xfcui/FlexFill.