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Free-Energy Simulations Support a Lipophilic Binding Route for Melatonin Receptors.

ABSTRACT: The effects of the neurohormone melatonin are mediated by the activation of the GPCRs MT₁ and MT₂ in a variety of tissues. Crystal structures suggest ligand access to the orthosteric binding site of MT₁ and MT₂ receptors through a lateral channel between transmembrane (TM) helices IV and V. We investigated the feasibility of this lipophilic entry route for 2-iodomelatonin, a nonselective agonist with a slower dissociation rate from the MT₂ receptor, applying enhanced sampling simulations and free-energy calculations. 2-Iodomelatonin unbinding was investigated with steered molecular dynamics simulations which revealed different trajectories passing through the gap between TM helices IV and V for both receptors. For one of these unbinding trajectories from the MT₁ receptor, an umbrella-sampling protocol with path-collective variables provided a calculated energy barrier consistent with the experimental dissociation rate. The side-chain flexibility of Tyr5.38 was significantly different in the two receptor subtypes, as assessed by metadynamics simulations, and during ligand unbinding it frequently assumes an open conformation in the MT₁ but not in the MT₂ receptor, favoring 2-iodomelatonin egress. Taken together, our simulations are consistent with the possibility that the gap between TM IV and V is a way of connecting the orthosteric binding site and the membrane core for lipophilic melatonin receptor ligands. Our simulations also suggest that the open state of Tyr5.38 generates a small pocket on the surface of MT₁ receptor, which could participate in the recognition of MT₁-selective ligands and may be exploited in the design of new selective compounds.

SUBMITTER: Elisi GM

PROVIDER: S-EPMC8757440 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The absolute (standard) binding free energy of eight FK506-related ligands to FKBP12 is calculated using free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent. A number of features are implemented to improve the accuracy and enhance the convergence of the calculations. First, the absolute binding free energy is decomposed into sequential steps during which the ligand-surrounding interactions as well as various biasing potentials restraining the translation, orientation, and conformation of the ligand are turned "on" and "off." Second, sampling of the ligand conformation is enforced by a restraining potential based on the root mean-square deviation relative to the bound state conformation. The effect of all the restraining potentials is rigorously unbiased, and it is shown explicitly that the final results are independent of all artificial restraints. Third, the repulsive and dispersive free energy contribution arising from the Lennard-Jones interactions of the ligand with its surrounding (protein and solvent) is calculated using the Weeks-Chandler-Andersen separation. This separation also improves convergence of the FEP/MD calculations. Fourth, to decrease the computational cost, only a small number of atoms in the vicinity of the binding site are simulated explicitly, while all the influence of the remaining atoms is incorporated implicitly using the generalized solvent boundary potential (GSBP) method. With GSBP, the size of the simulated FKBP12/ligand systems is significantly reduced, from approximately 25,000 to 2500. The computations are very efficient and the statistical error is small ( approximately 1 kcal/mol). The calculated binding free energies are generally in good agreement with available experimental data and previous calculations (within approximately 2 kcal/mol). The present results indicate that a strategy based on FEP/MD simulations of a reduced GSBP atomic model sampled with conformational, translational, and orientational restraining potentials can be computationally inexpensive and accurate.

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Free-Energy Simulations Support a Lipophilic Binding Route for Melatonin Receptors.

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