(A) TM6 inward-to-outward conformational transition observed in the inactive (PDB 5N2S) and active (PDB 6D9H) X-Ray and Cryo-EM structures. (B) Features used to follow the TM6 inward-to-outward …
The helices and loops of the A1R receptor are depicted with different colors while the heterotrimeric Gi2 protein is in gray. The Gαi2-α5 helix that binds into the intracellular cavity of the …
(A) Population analysis of the A1R activation obtained from conventional molecular dynamics (cMD) simulations starting from the inactive X-Ray and active Cryo-EM structures, the coordinates of the …
The lines represent the mean ΔΔG value of the 10 walker replicas along the simulation time. The energy differences between the inactive-active, inactive-intermediate, and active-intermediate energy …
(A) Plot showing that the multiple-walkers (W1-10) sampling covers the CV space. (B) For clarity, only two walkers (W1 and W2) are represented.
The free energy landscape is represented by a gray line while its associated error corresponds to the yellow-shaded area. The error was estimated using the block averaging technique, as described in …
The inactive X-Ray (PDB 5N2S) and active Cryo-EM (PDB 6D9H) structures are displayed in blue and magenta, respectively. The metrics used in this work are highlighted in spheres for the psi dihedral …
The original biased collective variables (CVs) are shown in purple while the unbiased CVs (i.e. the micro-switches) are in blue. The inactive and active regions of the CV space are highlighted. Note …
The reweighting analysis shows that the activation energy barrier associated with the free energy landscape (FEL) of CV1 and the PIF motif is similar to that of the original biased FEL (i.e. CV1 and …
The PEN identifies extra and intracellular communication centers together with the allosteric pathways that interconnect them. The PEN residues (nodes) are represented by colored spheres as a …
Representative structures from the broad range of conformations sampled by adenosine (ADO) in the metadynamics simulations are shown as gray sticks. The PEN residues (nodes) that perform transient …
(A) The PEN residues (nodes) are represented by colored spheres as a function of the receptor region (e.g. TM6 nodes in teal) while the allosteric pathways (edges) as yellow-orange sticks. The size …
The inactive, intermediate, and pre-active regions of the FEL are separated by black dashed lines. The number of structures associated with each conformational state is also shown.
The histograms corresponding to the inactive, intermediate, and pre-active states are colored blue, green, and pink, respectively. The ionic-lock dynamics reveals that E229-R108 is the strongest …
(A) Population analysis of A1R activation in the ADO-A1R-Gi2 complex obtained from conventional molecular dynamics (cMD) simulations. The TM6 torsion corresponds to the dihedral angle formed by the …
The PEN residues (nodes) are represented by colored spheres as a function of the receptor region (e.g. TM6 nodes in teal) while the allosteric pathways (edges) as yellow-orange sticks. The size of …
(A) Iso-surface representation of the normalized frequency map (set at Φi=0.2 iso-value) obtained from MDPocked in the inactive (blue), intermediate (teal), pre-active (violet), and fully-active …
Zoom view of the transient pockets and protein energy networks of the upper region of the receptor. Adenosine (ADO) in pocket B and the MIPS521 positive allosteric modulator (PAM) in pocket D, both …
The MIPS521 PAM is depicted in orange sticks while its interacting residues are colored as a function of the receptor region (e.g. TM6 nodes in teal). The experimentally identified allosteric …
ADO in pocket B and MIPS521 PAM in pocket D, both aligned from PDB 7LD3, are depicted in gray and orange sticks, respectively. Note that ADO and PAM sticks are displayed with transparency in the …
Population analysis of A1R activation in the A1R-Gi2 (left), ADO-A1R-Gi2 (middle), and PAM- ADO-A1R-Gi2 (right) complexes obtained from conventional molecular dynamics (cMD) simulations. The TM6 …
Transient pockets location and containing PEN residues in all conformational states.