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.

激酶是参与关键细胞途径调节的普遍存在的酶。但是，由于固有的局限性和计算方法的成本，很难对这些酶的构象进行计算机模拟。结合同源性建模和并行模拟的最新算法进展使研究人员能够解决此计算采样瓶颈。在这里，我们介绍了七个Src家族激酶（SFK）成员的分子动力学研究的结果：Fyn，Lyn，Lck，Hck，Fgr，Yes和Blk。我们提出了对Markov状态模型的序列不变扩展，这使我们能够定量比较这七个激酶的结构整体。我们的发现表明，在没有监管合作伙伴的情况下，SFK成员具有类似的计算机动力学，活跃状态的范围为4％至40％，激活时间尺度为数百微秒。此外，我们观察到了几种潜在的可药物介导的中间状态，包括可能通过小分子抑制剂靶向的三磷酸腺苷结合位点旁边的口袋。