On the other hand, the positive charges at the pY binding sites of the D1 and D2 domains are consistent with the competitive binding of substrates by the two domains of DLAR. MD simulations of the PTP domain models were used to understand the conformational basis of the interaction between the two PTP domains of DLAR and PTP99A. As the linker connecting the two PTP domains is crucial for maintaining the substrate specificity of the LAR and LCA RPTPs , it was speculated that movements in the linker, could, in principle, play a role in communication between the two PTP domains. The positioning of the linker at the backside of the D1 domains is an evolutionary hotspot harboring the allosteric site for modulation of activity in single domain PTPs . In the present studies, the minimal root mean square fluctuations in the linker region over simulation time suggests that the linker between the two domains is quite rigid. It thus appears likely that residues in the linker may not be solely responsible for domain-domain interactions. To evaluate the role of other conserved protein segments in inter-domain interactions, the inter-atomic network of the PTP domains were examined for each residue for each PTP domain. While the butterfly pattern of the PTP fold was observed in all the four PTP domains, alterations in the networks of functionally important residues could rationalize the differences in the biochemical properties of the PTP domains. We speculate that the smaller clusters in the D1 domain of PTP99A compared to that of DLAR could be correlated with the low intrinsic activity of the PTP99A protein. Differences in the network between the active site Arg, the general acid Asp, the Trp at the hinge and the peptide recognition residues between the D1 domains of DLAR and PTP99A reflect the differences in their substrate recognition features. Substitution of two critical amino acids, leading to the loss of activity in the D2 domains of the LAR family is reflected in the alterations in their inter-atomic networks . While the D2 domain of PTP99A also shows the sequence signatures within the butterfly pattern of the PTP fold, the disjoint hubs of residues implicated in substrate binding and catalysis Nutlin-3 Mdm2 inhibitor reveals smaller differences between this PTP domain and the others.