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GPCR Unbiased lipid-like ligand binding with ACEMD

By Franck Chevalier


The binding process through the membrane bilayer of lipid-like ligands to a GPCR protein target is an important but poorly explored recognition process at the atomic level. In this work ,the binding of the lipid inhibitor ML056 to the sphingosine-1-phosphate receptor 1 (S1P1R) has been successfully reported using unbiased molecular dynamics simulations with an aggregate sampling of over 800 μs. The binding pathway is a multi-stage process consisting of the ligand diffusing in the bilayer leaflet to contact a “membrane vestibule” at the top of TM 7, subsequently moving from this lipid-facing vestibule to the orthosteric binding cavity through a channel formed by TMs 1 and 7 and the N-terminal of the receptor. Unfolding of the GPCR N-terminal alpha-helix increases the volume of the channel upon ligand entry, helping to reach the crystallographic pose that also corresponds to the predicted favorable pose. The relaxation timescales of the binding process show that the binding of the ligand to the “membrane vestibule” is the rate-limiting step in the multi microseconds timescale. We comment on the significance and parallels of the binding process in the context of other binding studies.

Current challenges

Both ACEMD and HTMD software have permitted to perform the preparation, simulation and analysis of trajectories and elucidate the binding pathway along with critical atomic interactions and conformational changes. Similar to other studies of ligand binding to GPCRs4 , there is a barrier to binding that occurs far away from the final binding pose. This barrier is formed by the interaction between the zwitterionic head group of the ligand and R2927.34 and E2947.36 in the “membrane vestibule” and the desolvation necessary for the ligand to enter the channel.

A final barrier is due to rearrangements of the water molecules in the binding cavity and of dihedral angles in the head and tail of the ligand such that all these favorable interactions can be formed.

Along the binding process, the widening of the cavity by the flexible N-terminus and the desolvation of the ligand head group appear as general trends.



In this work,  the binding of a lipid-like ligand from the membrane bilayer directly to the orthosteric binding site of a GPCR using unbiased MD simulations has been shown. The ML056 inhibitor, studied here, binds S1P1R through a multi-step process that finally leads to the crystallographic binding pose.



Nathaniel Stanley, Leonardo Pardo & Gianni De Fabritiis, The pathway of ligand entry from the membrane bilayer to a lipid G protein-coupled receptor (GPCR), Scientific Reports 2016

Franck ChevalierGPCR Unbiased lipid-like ligand binding with ACEMD