6BL8

Predicting the Conformational Variability of Abl Tyrosine Kinase Using Molecular Dynamics Simulations and Markov State Models

Summary for 6BL8

• Entry DOI: 10.2210/pdb6bl8/pdb
• Descriptor: Tyrosine-protein kinase ABL1, PURVALANOL B, SULFATE ION, ... (4 entities in total)
• Functional Keywords: abl, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 64076.02

Authors

Clawson, D.K.,Gao, C. (deposition date: 2017-11-09, release date: 2018-03-07, Last modification date: 2024-03-06)

Primary citation

Meng, Y.,Gao, C.,Clawson, D.K.,Atwell, S.,Russell, M.,Vieth, M.,Roux, B.
Predicting the Conformational Variability of Abl Tyrosine Kinase using Molecular Dynamics Simulations and Markov State Models.
J Chem Theory Comput, 14:2721-2732, 2018

PubMed 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.

PubMed: 29474075
DOI: 10.1021/acs.jctc.7b01170

Experimental method

X-RAY DIFFRACTION (2.5 Å)