Capturing the Flexibility of a Protein-Ligand Complex: Binding Free Energies from Different Enhanced Sampling Techniques.
J Chem Theory Comput
; 16(7): 4615-4630, 2020 Jul 14.
Article
en En
| MEDLINE
| ID: mdl-32497432
ABSTRACT
Enhanced sampling techniques are a promising approach to obtain reliable binding free-energy profiles for flexible protein-ligand complexes from molecular dynamics (MD) simulations. To put four popular enhanced sampling techniques to a biologically relevant and challenging test, we studied the partial dissociation of an antigenic peptide from the Major Histocompatibility Complex I (MHC I) HLA-B*3501 to systematically investigate the performance of umbrella sampling (US), replica exchange with solute tempering 2 (REST2), bias exchange umbrella sampling (BEUS, or replica-exchange umbrella sampling), and well-tempered metadynamics (MTD). With regard to the speed of sampling and convergence, the peptide-MHC I complex (pMHC I) under study showcases intrinsic strengths and weaknesses of the four enhanced sampling techniques used. We found that BEUS can best handle the sampling challenges that arise from the coexistence of an enthalpically and an entropically stabilized free-energy minimum in the pMHC I under study. These findings might also be relevant for other flexible biomolecular systems with competing enthalpically and entropically stabilized minima.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antígeno HLA-B35
/
Ligandos
Idioma:
En
Revista:
J Chem Theory Comput
Año:
2020
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA