Predicting ligand binding poses for low-resolution membrane protein models: Perspectives from multiscale simulations

Abstract

Membrane receptors constitute major targets for pharmaceutical intervention. Drug design efforts rely on the identification of ligand binding poses. However, the limited experimental structural information available may make this extremely challenging, especially when only low-resolution homology models are accessible. In these cases, the predictions may be improved by molecular dynamics simulation approaches. Here we review recent developments of multiscale, hybrid molecular mechanics/coarse-grained (MM/CG) methods applied to membrane proteins. In particular, we focus on our in-house MM/CG approach. It is especially tailored for G-protein coupled receptors, the largest membrane receptor family in humans. We show that our MM/CG approach is able to capture the atomistic details of the receptor/ligand binding interactions, while keeping the computational cost low by representing the protein frame and the membrane environment in a highly simplified manner. We close this review by discussing ongoing improvements and challenges of the current implementation of our MM/CG code.

From quantum to subcellular scales: multi-scale simulation approaches and the SIRAH force field

“…MARTINI virtual sites [52], GROMOS/MARTINI [53] (http://cgmartini.nl) GROMACS (http://www.gromacs.org) [117] f GROMOS/Gō [76] modified version of GROMACS 4.5…”

Mutagenesis computer experiments in pentameric ligand-gated ion channels: the role of simulation tools with different resolution

“…Methods of different resolution can in principle be combined, not only at the QM/MM level already mentioned, but also at the MM/CG level, which have been recently tested for membrane proteins [116]. Mesoscopic and macroscopic levels may also be important to understand how pLGICs contribute to neuronal communication.…”

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

“…A region at the interface between the MM and CG parts couples the two levels of resolution (Figure 1). The membrane is described implicitly by introducing five potential walls (Leguèbe et al, 2012;Schneider et al, 2018). Two planar walls coincide with the height of the head groups of the membrane lipids, two hemispheric walls cap the extracellular and intracellular ends of the protein and prevent water evaporation, and the last wall follows the initial shape of the interface between protein and membrane, mimicking the effect of the lipid acyl tails (Figure 1).…”

“…In an effort at addressing this issue, we have developed a Hybrid Molecular Mechanics/Coarse-Grained (MM/CG) simulation approach ( Neri et al, 2005 , 2008 ; Leguèbe et al, 2012 ; Marchiori et al, 2013 ; Sandal et al, 2015 ; Capaldi et al, 2018 ; Alfonso-Prieto et al, 2019 ; Fierro et al, 2019 ). 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 ).…”