Abstract：
:Bruton tyrosine kinase (BTK) is a key enzyme in B-cell development whose improper regulation causes severe immunodeficiency diseases. Design of selective BTK therapeutics would benefit from improved, in-silico structural modeling of the kinase's solution ensemble. However, this remains challenging due to the immense computational cost of sampling events on biological timescales. In this work, we combine multi-millisecond molecular dynamics (MD) simulations with Markov state models (MSMs) to report on the thermodynamics, kinetics, and accessible states of BTK's kinase domain. Our conformational landscape links the active state to several inactive states, connected via a structurally diverse intermediate. Our calculations predict a kinome-wide conformational plasticity, and indicate the presence of several new potentially druggable BTK states. We further find that the population of these states and the kinetics of their inter-conversion are modulated by protonation of an aspartate residue, establishing the power of MD & MSMs in predicting effects of chemical perturbations.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Sultan MM,Denny RA,Unwalla R,Lovering F,Pande VSdoi
10.1038/s41598-017-10697-0subject
Has Abstractpub_date
2017-11-15 00:00:00pages
15604issue
1issn
2045-2322pii
10.1038/s41598-017-10697-0journal_volume
7pub_type
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