Transmembrane dimers of type 1 receptors sample alternate configurations: MD simulations using coarse grain Martini 3 versus AlphaFold2 Multimer

Structures and dynamics of transmembrane (TM) receptor regions are key to understanding their signaling mechanism across membranes. Here we examine configurations of TM region dimers, assembled using the recent Martini 3 force field for coarse-grain (CG) molecular dynamics simulations. At first glance, our results show only a reasonable agreement with ab initio predictions using PREDDIMER and AlphaFold2 Multimer and with nuclear magnetic resonance (NMR)-derived structures. 5 of 11 CG TM structures are similar to the NMR structures (within <3.5 A root-mean-square deviation [RMSD]) compared with 10 and 9 using PREDDIMER and AlphaFold2, respectively (with 8 structures of the later within 1.5 A). Surprisingly, AlphaFold2 predictions are closer to NMR structures when the 2001 instead of 2020 database is used for training. The CG simulations reveal that alternative configurations of TM dimers readily interconvert with a predominant population. The implications for transmembrane signaling are discussed, including for the development of peptide-based pharmaceuticals.

Automated summary

The structures and dynamics of transmembrane (TM) receptor regions play a crucial role in understanding how signaling occurs across membranes. In this study, the configurations of TM region dimers were investigated using CG molecular dynamics simulations with the Martini 3 force field. The results showed a reasonable agreement with ab initio predictions and NMR-derived structures, with some differences observed between the different prediction methods. The implications of these findings for transmembrane signaling and peptide-based pharmaceutical development are discussed.