Community analysis of large‐scale molecular dynamics simulations elucidated dynamics‐driven allostery in tyrosine kinase 2

Abstract

AbstractTYK2 is a nonreceptor tyrosine kinase, member of the Janus kinases (JAK), with a central role in several diseases, including cancer. The JAKs' catalytic domains (KD) are highly conserved, yet the isolated TYK2‐KD exhibits unique specificities. In a previous work, using molecular dynamics (MD) simulations of a catalytically impaired TYK2‐KD variant (P1104A) we found that this amino acid change of its JAK‐characteristic insert (αFG), acts at the dynamics level. Given that structural dynamics is key to the allosteric activation of protein kinases, in this study we applied a long‐scale MD simulation and investigated an active TYK2‐KD form in the presence of adenosine 5′‐triphosphate and one magnesium ion that represents a dynamic and crucial step of the catalytic cycle, in other protein kinases. Community analysis of the MD trajectory shed light, for the first time, on the dynamic profile and dynamics‐driven allosteric communications within the TYK2‐KD during activation and revealed that αFG and amino acids P1104, P1105, and I1112 in particular, hold a pivotal role and act synergistically with a dynamically coupled communication network of amino acids serving intra‐KD signaling for allosteric regulation of TYK2 activity. Corroborating our findings, most of the identified amino acids are associated with cancer‐related missense/splice‐site mutations of the Tyk2 gene. We propose that the conformational dynamics at this step of the catalytic cycle, coordinated by αFG, underlie TYK2‐unique substrate recognition and account for its distinct specificity. In total, this work adds to knowledge towards an in‐depth understanding of TYK2 activation and may be valuable towards a rational design of allosteric TYK2‐specific inhibitors.