Figure 2. MD simulations applied to study the energetics of large scale structural transition in an explicit membrane/solvent environment.

(A) GlpT in an inward facing (IF) open conformation is represented as cartoon, embedded in an explicit lipid bilayer which is shown in surface representation. The helices involved in biasing the transition are shown as pink and blue cartoon. (B) Schematic representation of the states involved in the thermodynamic cycle studied (colored as in A). (C) Free energy profile along the thermodynamic cycle shown in (A), involving both apo (red) and bound (green) GlpT. The free energy along the transition pathway (discretized into 150 images/windows) was computed employing an umbrella sampling method. The free energy calculations identify all the intermediate states involved in the transport cycle and show that the apo transition is unfavorable while the transition of the phosphate-bound (P_i-bound) state is feasible. (D) Potential of mean force (PMF) projected along the two reaction coordinates, showing two distinct pathways in red and blue. The blue pathway is the lower free energy pathway explaining the energetics of allowed GlpT transition in the presence of the substrate P_i. The red pathway, on the other hand, is a higher free energy pathway that explains forbidden transition of GlpT in the absence of substrate. Adapted with permission from ref [42]. Copyright 2015 Moradi et al. Licensed under a Creative Commons Attribution 4.0 International License.