Internal strain regulates the nucleotide binding site of the kinesin leading head.

In the presence of ATP, kinesin proceeds along the protofilament of microtubule by alternated binding of two motor domains on the tubulin binding sites. Because the processivity of kinesin is much higher than other motor proteins, it has been speculated that there exists a mechanism for allosteric regulation between the two monomers. Recent experiments suggest that ATP binding to the leading head (L) domain in kinesin is regulated by the rearward strain built on the neck-linker. We test this hypothesis by explicitly modeling a Calpha-based kinesin structure whose motor domains are bound on the tubulin binding sites. The equilibrium structures of kinesin on the microtubule show disordered and ordered neck-linker configurations for the L and trailing head, respectively. The comparison of the structures between the two heads shows that several native contacts present at the nucleotide binding site in the L are less intact than those in the binding site of the rear head. The network of native contacts obtained from this comparison provides the internal tension propagation pathway, which leads to the disruption of the nucleotide binding site in the L. Also, using an argument based on polymer theory, we estimate the internal tension built on the neck-linker to be f approximately 12-15 pN. Both of these conclusions support the experimental hypothesis.