PMC

A comparison between approximations of the smallest explicit atomistic system setup of a GPCR protomer (e.g., []) and the largest CG setup of the simulations [] surveyed in this manuscript. The protomers are shown in blue, and the lipids are shown in grey (hydrophobic tails) and red/orange (head groups).

Scatter plot of simulation length vs. simulation size for studies reviewed in this manuscript. The blue arrow indicates the direction of increasing experimental timescales and a comparison of the time step for atomistic and for CG simulations is highlighted. Atomistic simulations reviewed here are represented by green triangles, CG simulations by red crosses and biased simulations by blue circles. Where multiple simulations were performed in the same publication, the total time used for the analysis of the single system is reported. For instance, for the biased umbrella sampling, the total time is the sum of the lengths of all windows, whereas for multiple simulations of different systems only the longest is reported in this graph.

Three key events in the life of a GPCR. The leftmost panel illustrates ligand recognition, showing the exit pathways of carazolol (black, stick representation) from the crystallographically found binding site in the β2AR (rainbow blue to red by residue number, cartoon representation, viewed from the extracellular side) as determined by the RAMD study [] reviewed here. The size of the arrow denotes the approximate relative frequency of occurrence of each of the exit pathways during the RAMD. Arrow A is the major exit pathway found by RAMD, and is highlighted as the closest equivalent to the entry pathway observed for NLX into the binding pocket of the DOR, in the cited WTM study []. Arrow B is highlighted as the exit pathway found by RAMD that is the closest equivalent to the entry pathway of 2-AG into the cannabinoid receptor, via a cleft between TM6 and TM7, suggested in []. The central panel illustrates the largest conformational changes occurring activation using an intracellular view of the aligned structures of inactive rhodopsin (PDBid: 1GZM) [] and metarhodopsin II (PDBid: 3PXO) []. Changes highlighted in the activated structure are the movement of TM6 by ~ 6Å, movement and torsion of TM5. The right-most panel shows a system setup for a coarse-grained simulation of a GPCR homodimer, in an explicit lipid environment. Water is shown in blue, the phosphocholine bilayer is shown in grey (hydrophobic tails) and red/orange (head groups), cholesterol is yellow and the two protomers are shown in red and green.