Cells sense their environment and adhere to substrates with the help of cell surface receptors,integrins. The activity of integrins is controlled by talin, a large intracellular adaptor proteinbinding to the cytoplasmic tail of integrin. Talin both activates integrin and connects it to theforce-bearing machinery of the cell. The talin-integrin complex mediates mechanical signalsbetween the extracellular matrix and the intracellular actin cytoskeleton, and the tensiondictates the coupling of further adaptor and signaling proteins to talin. These mechanical andbiochemical signals affect the shape and motion of the cell, and regulate gene expression.Despite numerous studies on talin-integrin interactions, it is not yet fully clear how talinactivates integrin, and the complete structure of the integrin-binding talin head domainremains to be solved.In this thesis I focus on the interactions of integrin and the talin head domain using moleculardynamics simulations. In the first study we analyzed how mechanical load affects the talin-integrin binding interface in a set of constant force pulling simulations. We found that themechanical stability of the talin-integrin interface requires a set of anti-parallel β-sheet-likehydrogen bonds, but not the binding of the β-integrin NPxY motif.In the second and third studies, we studied the talin-αIIbβ3 integrin complex in the presenceof a lipid bilayer. These simulations were carried out using two different talin models: anextended talin head conformation based on a published crystallographic structure, and ourproposed compact talin conformation, whose design is based on homologous 3-D structures.Simulations of the extended talin conformation showed that the integrin dimer could becomeperturbed, and even activated, by acidic phospholipids in the cell membrane. With our own,compact domain model, our MD simulations predicted an interaction between a flexible loopand integrin. Experiments carried outin vitro andin cellulo supported the proposed compactconformation of the talin head and provided evidence for the predicted interaction betweenthe talin loop and integrin
