General Metadynamics Protocol To Simulate Activation/Deactivation of Class A GPCRs: Proof of Principle for the Serotonin Receptor.
J Chem Inf Model
; 63(10): 3105-3117, 2023 05 22.
Article
em En
| MEDLINE
| ID: mdl-37161278
ABSTRACT
We present a generally applicable metadynamics protocol for characterizing the activation free-energy profiles of class A G-protein coupled receptors and a proof-of-principle study for the 5HT1A-receptor. The almost universal A100 activation index, which depends on five inter-helix distances, is used as the single collective variable in well-tempered multiple-walker metadynamics simulations. Here, we show free-energy profiles for the serotonin receptor as binary (apo-receptor + G-protein-α-subunit and receptor + ligand) and ternary complexes with two prototypical orthosteric ligands the full agonist serotonin and the partial agonist aripiprazole. Our results are not only compatible with previously reported experimental and computational data, but they also allow differences between active and inactive conformations to be determined in unprecedented atomic detail, and with respect to the so-called microswitches that have been suggested as determinants of activation, giving insight into their role in the activation mechanism.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores Acoplados a Proteínas G
/
Simulação de Dinâmica Molecular
Idioma:
En
Revista:
J Chem Inf Model
Assunto da revista:
INFORMATICA MEDICA
/
QUIMICA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Alemanha