Towards a Fundamental Understanding of the Mechanisms of Mechanotransduction Through Focal Adhesion Proteins

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1133351MoonApplied loads - even those in the sub-unfolding regime?transmitted through proteins can significantly alter the proteins - conformations and chemical behavior, yet essential details of how and where mechanical load manifests itself inside proteins remain unclear. Given the intrinsic duality between a protein's free energy landscape and its chemical reactive potential, knowledge of strain energy storage is key to understanding of the coupled mechano-chemo behavior of proteins; ultimately holding the key to unveiling the fundamental mechanisms of mechanotransduction in proteins. Towards these ends, load transmissions within the three major domains of Focal Adhesion Kinase (FAK) are studied via steered molecular dynamics simulations. Progressively higher constant loads are applied to: (i) constituent secondary motifs, and (ii) entire domains, to provide insight into the changes in structural and vibrational characteristics, as well as the altered chemical behavior, of the major domains. As a key regulator of cellular processes central to tumorigenesis, metastasis and survival signaling, FAK has been identified as a potential target for anti-cancer drugs. Knowledge of how focal adhesion (FA) proteins perform their presumed roles in signal transmission is key to advancing the understanding of various signaling/regulatory pathways and, particularly in case of disease, to identifying potential molecular "targets" for therapeutic agents/treatments. Insights harnessed will help identify viable - perhaps even mechanically induced - targets for chemotherapy that are specifically designed to avoid systemic issues associated with complete "knock-out" of vital FA proteins like FAK. Beyond FAK, some of the basic operating principles underlying cellular signaling/regulatory pathways reliant on mechanical load are explained.