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. 2019 Jul 22;47(16):8675–8692. doi: 10.1093/nar/gkz613

Figure 5.

Figure 5.

RAM-dependent modulation of the RNMT active site conformations. (A) Definition of collective variables (CVs) used to construct the free energy landscape (FEL) of RNMT. CV1 describes the cap binding pocket accessibility and is defined as the centre of mass (COM) distance between the upper half of the RNMT α-helix A (residues 2–11, highlighted in dark-blue) and the β8-β9 loop (residues 362–366, in cyan). CV2 describes the AdoMet binding pocket accessibility and is defined as the COM distance between Motif I (residues 205–209, in red) and the β4-αD loop (residues 285–289, in orange). (B–E) The conformational FELs of the active site of RNMT calculated for the simulation systems: (B) RNMT–RAM complex with the bound substrates AdoMet and cap; (C) apo-RNMT; (D) apo-RNMT in complex with RAM; and (E) RNMT-RAM complex with the bound cap. The FELs were built using all the snapshots from the corresponding aMD simulation and are shown as 2D contour plots with the lines in 0.5 kcal/mol increments. The colour scale corresponding to (unweighted) free energies is shown at the top. The simulation system is indicated by a legend in the box below the FEL. The most sampled conformational states, corresponding to the FEL minima, are labelled, and the corresponding representative structures of the RNMT active site are shown in the middle and right panels, next to the FELs.