Predicting the Conformational Variability of Abl Tyrosine Kinase using Molecular Dynamics Simulations and Markov State Models.
J Chem Theory Comput
; 14(5): 2721-2732, 2018 May 08.
Article
em En
| MEDLINE
| ID: mdl-29474075
ABSTRACT
Understanding protein conformational variability remains a challenge in drug discovery. The issue arises in protein kinases, whose multiple conformational states can affect the binding of small-molecule inhibitors. To overcome this challenge, we propose a comprehensive computational framework based on Markov state models (MSMs). Our framework integrates the information from explicit-solvent molecular dynamics simulations to accurately rank-order the accessible conformational variants of a target protein. We tested the methodology using Abl kinase with a reference and blind-test set. Only half of the Abl conformational variants discovered by our approach are present in the disclosed X-ray structures. The approach successfully identified a protein conformational state not previously observed in public structures but evident in a retrospective analysis of Lilly in-house structures the X-ray structure of Abl with WHI-P154. Using a MSM-derived model, the free energy landscape and kinetic profile of Abl was analyzed in detail highlighting opportunities for targeting the unique metastable states.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Health_economic_evaluation
/
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article