Paper Citing NAMD - Abstract
Chipot, Christophe
Milestones in the Activation of a G Protein-Coupled Receptor. Insights from Molecular-Dynamics Simulations into the Human Cholecystokinin Receptor-1
JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 4:2150-2159, DEC 2008
Activation of G protein-coupled receptors (GPCRs) obeys an allosteric mechanism triggered by ligand binding. To understand how the signal is transduced in the cell, identification of the milestones paving the pathway between the active and the inactive states of the receptor is necessary. A model of the human cholecystokinin receptor-1 (CCK1R) has been proposed recently. The complex formed by CCK1R and an agonist ligand will serve as a paradigm of an active conformation to capture milestones in GPCR activation. To reach this goal, assuming microreversibility, the initial step toward the inactivation of CCK1R was modeled using free energy calculations, whereby the ligand is removed from the binding pocket. However accurate the reproduction of the experimental affinity constant, this simulation only represents an embryonic stage of the inactivation process. Starting from the apo receptor, an unprecedented 0.1-mu s molecular dynamics trajectory was generated, bereft of experimental biases, bringing into the light key events in the inactivation of CCK1R, chief among which the hydration of its internal cavity, concomitant with the spatial rearrangement of the transmembrane helical segments. Hydration is intimately related to the isomerization of the highly conserved residue W326 of helix VI, acting as a two-state toggle switch, and of residue M121 of helix III. In the active state, the former residue obstructs the crevice, thereby preventing water leakage, which would otherwise trigger the disruption of an ionic lock between helices II and III involving the signature E/DRY motif ubiquitous to GPCRs.
