P176S Mutation Rewires Electrostatic Interactions That Alter Maspin Functionality

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 explainingits conflicting roles. Moreover, polymorphic forms of maspin havealso been linked to tumor regression and survival; for instance, maspinwith Ser at 176 (maspin-S176) promotes tumors, while maspin with Proat 176 (maspin-P176) has opposing roles in cancer pathogenesis. Withthe help of long molecular dynamics simulations, a possible link betweenpolymorphic 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 electrostaticenergetics of various residues; finally, these altered electrostaticsof maspin-S176 and maspin-P176 rewire the polar contacts that abolishedthe allosteric control of the protein. By combining these factors,the altered electrostatics substantially affect the localization andpreference of maspin-binding partners, thus culminating in a differentmaspin-protein(cofactor)-interaction landscape that may have beenmanifested in previous conflicting reports. Here, the underlying reasonhas been highlighted and discussed, which may be helpful for bettertherapeutic manipulation.