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.

CGMD Platform: Integrated Web Servers for the Preparation, Running, and Analysis of Coarse-Grained Molecular Dynamics Simulations

“…CGMD techniques have been shown to be useful for gaining deeper insights into the mechanisms underlying the function of these systems at time/space-scales that cannot be studied at an atomistic resolution. Due to increasing interest and the availability of more powerful algorithms and hardware, in recent years, several web servers have been developed with the scope to prepare and/or perform different resolution levels of MD simulations, i.e., CHARMM-GUI [ 42 ], CABS-flex [ 43 ], locPREFMD [ 44 ], MDWeb [ 45 ], PREFMD [ 46 ], ProBLM [ 47 ], SMOG [ 48 ], UNRES [ 49 ], Vienna-PTM [ 50 ], MM/CG web server [ 51 ]. In particular, the existing web servers provide a web-based graphical user interface to generate various molecular simulation systems and input files to facilitate the usage of common simulation techniques.…”

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

“…Indeed, the OB-MM/CG improves the description of the structural and dynamical properties of water, thus enabling a rigorous implementation of free-energy methods. The MM/CG code is freely available on the Hybrid MM/CG webserver (; see the Download section) …”

“…grs.kfa-juelich.de/; see the Download section). 119 ■ ASSOCIATED CONTENT * sı Supporting Information…”

From System Modeling to System Analysis: The Impact of Resolution Level and Resolution Distribution in the Computer-Aided Investigation of Biomolecules

“…Atomistic water molecules in the extracellular side, hydrating the binding site, are confined by a repulsive potential. This approach has been widely tested on bitter taste receptor GPCRs ( Schneider et al, 2018 ; Fierro et al, 2019 ), and recently implemented in a webserver pipeline ( Schneider et al, 2020 ).…”