Tyrosine kinases: complex molecular systems challenging computational methodologies

Classical molecular dynamics (MD) simulations based on atomic models play an increasingly important role in a wide range of applications in physics, biology, and chemistry. Nonetheless, generating genuine knowledge about biological systems using MD simulations remains challenging. Protein tyrosine kinases are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Due to the large conformational changes and long timescales involved in their function, these kinases present particularly challenging problems to modern computational and theoretical frameworks aimed at elucidating the dynamics of complex biomolecular systems. Markov state models have achieved limited success in tackling the broader conformational ensemble and biased methods are often employed to examine specific long timescale events. Recent advances in machine learning continue to push the limitations of current methodologies and provide notable improvements when integrated with the existing frameworks. A broad perspective is drawn from a critical review of recent studies. Graphic abstract