The changes in accessibility of these binding sites and the subsequent binding or ejection of ligands, produces talin’s signalling response 7. The surface of these alpha-helix bundles contain protein binding sites which are accessible while a bundle is folded, whilst inside the bundles cryptic binding sites exist which are only made accessible once a bundle has unfolded. Talin’s rod domain contains 13 alpha-helix coiled-coils or ‘bundles’, which unfold if the tension applied to them exceeds a specific threshold. A key element of this process are mechanosensitive proteins such as talin that provide a physical interface between the external environment of the platelet and the internal cytoskeleton and the contractile machinery, by sensing and adapting to forces exerted on the platelet 3, 4, 5, 6. Platelets close vascular injury by aggregating, forming thrombi and then contracting 1, 2. This targeted, force-based simulation is, therefore, able to produce more realistic forces values than previous simulation methods. This covers the range of forces talin operates in and is 2–3 orders of magnitude closer to experimentally measured values than the compared all-atom and coarse-grained molecular dynamics. The results of the electrostatic approximation using Coulomb’s law shows a simulated force interaction within the physiological relevant range of 5–40 pN for the rod sub-domains of talin. Coordinate frames were used efficiently to compartmentalise the simulation structures and static analysis was applied to determine the propagation of forces and torques through the protein structure. Along with a corresponding alpha-helix modelling method, the simulation framework was developed drawing on robotic kinematics to specifically target force interactions. To overcome the current limitations of force measuring in molecular dynamics simulations, a new simulation framework was developed which operated directly within the force domain. A better understanding of talin unfolding events and the forces that are involved should allow better prediction of talin signalling.
The alpha-helix coiled-coils within talin’s rod domain have mechanical and signalling functions through their unfolding and refolding dynamics.