Ligand Pose Predictions for Human G Protein-Coupled Receptors: Insights from the Amber-Based Hybrid Molecular Mechanics/Coarse-Grained Approach

Abstract

Human G protein-coupled receptors (hGPCRs) are the most frequent targets of Food and Drug Administration (FDA)-approved drugs. Structural bioinformatics, along with molecular simulation, can support structure-based drug design targeting hGPCRs. In this context, several years ago, we developed a hybrid molecular mechanics (MM)/coarse-grained (CG) approach to predict ligand poses in low-resolution hGPCR models. The approach was based on the GROMOS96 43A1 and PRODRG united-atom force fields for the MM part. Here, we present a new MM/CG implementation using, instead, the Amber 14SB and GAFF all-atom potentials for proteins and ligands, respectively. The new implementation outperforms the previous one, as shown by a variety of applications on models of hGPCR/ligand complexes at different resolutions, and it is also more user-friendly. Thus, it emerges as a useful tool to predict poses in low-resolution models and provides insights into ligand binding similarly to all-atom molecular dynamics, albeit at a lower computational cost.

Hybrid MM/CG Webserver: Automatic Set Up of Molecular Mechanics/Coarse-Grained Simulations for Human G Protein-Coupled Receptor/Ligand Complexes

“…The hybrid MM/CG protocol has been successfully used to predict ligand poses in a variety of hGPCRs (Leguèbe et al, 2012;Marchiori et al, 2013;Sandal et al, 2015;Fierro et al, 2017;Capaldi et al, 2018;Fierro et al, 2019). Moreover, the Amber-based MM/CG poses improved significantly relative to those obtained by simple docking, especially for low resolution starting models (Schneider et al, 2020). However, the setup of such simulations has been time-consuming and system-dependent.…”

“…These include the adenosine 2A receptor in complex with caffeine (i.e., the example case of the webserver), the human bitter receptor 16 in complex with phenyl-β-D-glucopyranoside, the β2-adrenergic receptor with adrenaline, and the dopamine D3 receptor with eticlopride. The structures of these hGPCR/ligand complexes were either experimentally determined, taken from all-atom MD trajectories or predicted based on templates with decreasing resolution, up to extremely low sequence identity (<15%) (Schneider et al, 2020). Retrospective validation against available X-ray structures and mutagenesis data confirmed that the MM/CG approach can predict correct ligand poses and identify experimentally determined binding residues 2 (Schneider et al, 2020), regardless of the model resolution.…”

“…The structures of these hGPCR/ligand complexes were either experimentally determined, taken from all-atom MD trajectories or predicted based on templates with decreasing resolution, up to extremely low sequence identity (<15%) (Schneider et al, 2020). Retrospective validation against available X-ray structures and mutagenesis data confirmed that the MM/CG approach can predict correct ligand poses and identify experimentally determined binding residues 2 (Schneider et al, 2020), regardless of the model resolution. In addition, the MM/CG simulations can provide insights into the flexibility 1 https://gpcrdb.org/structure/statistics as of June 2020.…”

“…The receptor/ligand interactions are described in atomistic detail, including explicit water molecules in the binding site (MM region), while the rest of the receptor is coarse-grained (CG region) (Schneider et al, 2018). The all-atom force fields used (Schneider et al, 2020) for the MM part of the protein and water are the Amber14SB (Maier et al, 2015) and TIP3P (Jorgensen et al, 1983), respectively, whereas the ligand can be described using either GAFF or GAFF2 (Wang et al, 2004;Case et al, 2020). The CG region is described by a Gō-like (Gō and Abe, 1981) potential.…”

“…The scheme can be used also for GPCRs other than those from Homo sapiens. This approach turned out to be able to reproduce the ligand poses for four different hGPCRs (Schneider et al, 2020). These include the adenosine 2A receptor in complex with caffeine (i.e., the example case of the webserver), the human bitter receptor 16 in complex with phenyl-β-D-glucopyranoside, the β2-adrenergic receptor with adrenaline, and the dopamine D3 receptor with eticlopride.…”