Influence of Linker Flexibility on the Binding Affinity of Bidentate Binders

The design of responsive nanosensors typically relies on the availability of probes capable of capturing their target with high affinity and specificity. This can be achieved by coupling two or more binding units through a linker. In this work, we study the dependence on the binder architecture of the binding affinity between a target molecule and a semirigid bidentate binder. Using two different binder architectures, central-rigid and extreme-rigid, and modifying the length and the flexibility degree of the linker we generated 153 different architectures. We computed their dissociation free energies by means of Monte Carlo simulations and thermodynamic integration. We found that central-rigid bidentate binders are a poor choice, as they dissociate more easily than analogous fully flexible bidentate binders. On the other hand, molecular architectures presenting extreme-rigid units were shown effective for a wide range of set-ups.