Conformational Transitions upon Ligand Binding: Holo-Structure Prediction from Apo Conformations

TLDR

Protein function often depends on ligand‑induced complexes, but experimentally determining these complexes is costly, and current docking methods struggle with receptor flexibility, making accurate holo models essential yet difficult when only apo structures are available. The authors propose a method that predicts protein/ligand complex structures using only the apo structure, the ligand, and the holo radius of gyration. They applied the method to ten proteins exhibiting up to 7.1 Å backbone RMSD upon ligand binding. The approach achieved receptor models within 1.6 Å RMSD of the true holo structures and produced near‑native ligand poses in 8 of 10 top‑ranked complexes.

Abstract

Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein/ligand complexes, particularly docking, are as yet restricted by their limited consideration of receptor flexibility, rendering them not applicable for predicting protein/ligand complexes if large conformational changes of the receptor upon ligand binding are involved. Accurate receptor models in the ligand-bound state (holo structures), however, are a prerequisite for successful structure-based drug design. Hence, if only an unbound (apo) structure is available distinct from the ligand-bound conformation, structure-based drug design is severely limited. We present a method to predict the structure of protein/ligand complexes based solely on the apo structure, the ligand and the radius of gyration of the holo structure. The method is applied to ten cases in which proteins undergo structural rearrangements of up to 7.1 Å backbone RMSD upon ligand binding. In all cases, receptor models within 1.6 Å backbone RMSD to the target were predicted and close-to-native ligand binding poses were obtained for 8 of 10 cases in the top-ranked complex models. A protocol is presented that is expected to enable structure modeling of protein/ligand complexes and structure-based drug design for cases where crystal structures of ligand-bound conformations are not available.