Fig. 5: CCR5 and CXCR4 dimerization mechanism.

Representation of the BFES and the structures of the metastable states and minima identified for each system. A CCR5–CCR5. B CXCR4–CXCR4. C CCR5–CXCR4. In the case of CCR5–CXCR4 heterodimer, CCR5 is reported on the left, whereas CXCR4 is on the right. The lowest energy basins of each system on the BFES are highlighted by the A and B white letters, whereas the position of the metastable states is reported using white Greek letters. White crosses highlight the position on the BFES of the experimentally resolved CCR5 and CXCR4 homodimers. For each BFES, the lowest energy paths (LEPs) computed from the MetaD–CG calculations starting from each minimum or metastable state are reported as black, red, or purple solid lines. The transitions between metastable states and energy minima identified by the LEP are represented using arrows of matching colors connecting the structures depicted in cartoons on the top and bottom of each BFES. D Comparison of metastable dimeric states identified by CG–MetaD with the following X-ray structures: (Left) CCR5 dimer in 4MBS¹⁹ (RMSD 0.17 nm); (Center) CXCR4 dimer in 3OE9²¹ (RMSD 0.30 nm); (Right) CXCR4 trimer in 3OE8²¹ (chain A and B) (RMSD 0.29 nm). RMSD was computed on the Cα atoms of TM helices. Here, the bulky crystallization adjuvant molecules bound to the intracellular part of CCR5 and CXCR4 are omitted for clarity, while they are displayed in Supplementary Fig. 12. Experimental structures are represented as gray cartoons, whereas the CG–MetaD structures are displayed as color coded cartoons.