Abstract
Maspin is known to regress tumors by inhibiting angiogenesis; however, its roles have been reported to be context- and sequence-dependent. Various proteins and cofactors bind to maspin, possibly explaining its conflicting roles. Moreover, polymorphic forms of maspin have also been linked to tumor regression and survival; for instance, maspin with Ser at 176 (maspin-S176) promotes tumors, while maspin with Pro at 176 (maspin-P176) has opposing roles in cancer pathogenesis. With the help of long molecular dynamics simulations, a possible link between polymorphic forms and tumor progression has been established. First, maspin is dynamically stable with either amino acid at the 176 position. Second, differential contacts have been observed among various regions; third, these contacts have significantly altered the electrostatic energetics of various residues; finally, these altered electrostatics of maspin-S176 and maspin-P176 rewire the polar contacts that abolished the allosteric control of the protein. By combining these factors, the altered electrostatics substantially affect the localization and preference of maspin-binding partners, thus culminating in a different maspin-protein(cofactor)-interaction landscape that may have been manifested in previous conflicting reports. Here, the underlying reason has been highlighted and discussed, which may be helpful for better therapeutic manipulation.