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 Å root-mean-square deviation [RMSD]) compared with 10 and 9 using PREDDIMER and AlphaFold2, respectively (with 8 structures of the later within 1.5 Å). 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.

跨膜 (TM) 受体区域的结构和动力学是理解其跨膜信号传导机制的关键。在这里，我们检查了 TM 区域二聚体的配置，这些二聚体使用最近的 Martini 3 力场进行组装，用于粗粒 (CG) 分子动力学模拟。乍一看，我们的结果仅显示与使用 PREDDIMER 和 AlphaFold2 多聚体的从头计算预测以及核磁共振 (NMR) 衍生的结构合理一致。 11 个 CG TM 结构中有 5 个与 NMR 结构相似（均方根偏差小于 3.5 Å 以内），而分别使用 PREDDIMER 和 AlphaFold2 得到的 10 个和 9 个结构与 NMR 结构相似（后者的 8 个结构在 1.5 Å 以内）。令人惊讶的是，当使用 2001 年而不是 2020 年数据库进行训练时，AlphaFold2 的预测更接近 NMR 结构。 CG 模拟表明，TM 二聚体的替代构型很容易与主要群体相互转化。讨论了跨膜信号转导的影响，包括基于肽的药物的开发。