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

Abstract

Hybrid Molecular Mechanics/Coarse-Grained (MM/CG) simulations help predict ligand poses in human G protein-coupled receptors (hGPCRs), the most important protein superfamily for pharmacological applications. This approach allows the description of the ligand, the binding cavity, and the surrounding water molecules at atomistic resolution, while coarse-graining the rest of the receptor. Here, we present the Hybrid MM/CG Webserver (mmcg.grs.kfa-juelich.de) that automatizes and speeds up the MM/CG simulation setup of hGPCR/ligand complexes. Initial structures for such complexes can be easily and efficiently generated with other webservers. The Hybrid MM/CG server also allows for equilibration of the systems, either fully automatically or interactively. The results are visualized online (using both interactive 3D visualizations and analysis plots), helping the user identify possible issues and modify the setup parameters accordingly. Furthermore, the prepared system can be downloaded and the simulation continued locally.

Keywords: G protein-coupled receptor; MM/CG; coarse-grained; hybrid methods; ligand; molecular dynamics simulation; molecular mechanics; webserver.

FIGURE 1

Hybrid MM/CG scheme. The three regions (MM, I, and CG) are framed with different background colors and the five potential walls (upper and lower hemispheres, upper and lower membrane planes, and membrane surface) are indicated with black lines.

FIGURE 2

Webserver workflow. Interactive mode with manual intervention is presented on the left and fast automatic mode on the right.

FIGURE 3

Sample 3D visualizations created by the webserver using as example the hA_2AR/CFF complex. (A–C) Full view of the hGPCR/ligand complex and (D–F) close-up view of the ligand and its interactions with protein and water molecules. Images were generated with the screenshot tool in the NGL viewer (Jakalian et al., 2004) used in the “Results” section of the webserver. Atoms are colored using the default NGL color code and ligand interactions are determined using the default NGL definition.