Abstract
Kinases are ubiquitous enzymes involved in the regulation of critical cellular pathways. However, in silico modelling of the conformational ensembles of these enzymes is difficult due to inherent limitations and the cost of computational approaches. Recent algorithmic advances combined with homology modelling and parallel simulations have enabled researchers to address this computational sampling bottleneck. Here, we present the results of molecular dynamics studies for seven Src family kinase (SFK) members: Fyn, Lyn, Lck, Hck, Fgr, Yes and Blk. We present a sequence invariant extension to Markov state models, which allows us to quantitatively compare the structural ensembles of the seven kinases. Our findings indicate that in the absence of their regulatory partners, SFK members have similar in silico dynamics with active state populations ranging from 4 to 40% and activation timescales in the hundreds of microseconds. Furthermore, we observe several potentially druggable intermediate states, including a pocket next to the adenosine triphosphate binding site that could potentially be targeted via a small-molecule inhibitor.
Highlights
Protein kinases are important pharmaceutical targets[1,2] due to their regulatory roles in biochemical pathways in eukaryotic cells[3]
Unbiased, multi-millisecond molecular dynamics (MD) dynamics of seven Src family kinase (SFK) members presented here have provided us with detailed atomistic insight into their collective activation mechanisms, revealing the prominence of Hinge motion for activation
Our Fyn Markov state models (MSMs) suggests that the catalytic domain, in the absence of its 10
Summary
Protein kinases are important pharmaceutical targets[1,2] due to their regulatory roles in biochemical pathways in eukaryotic cells[3]. They control a slew of signaling cascades by catalyzing the transfer of γ-phosphate from adenosine triphosphate (ATP) to target substrates[4]. Kinases are thought to account for up to 2% of all encoded genes[5]. Given their physiological role, kinase functionality within cells is tightly monitored.[4,6] Mutations, 1.
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