Combining measurements to estimate properties and characterization extent of complex biochemical mixtures; applications to Heparan Sulfate.
Complex mixtures of molecular species, such as glycoproteins and glycosaminoglycans, have important biological and therapeutic functions. Characterization of these mixtures with analytical chemistry measurements is an important step when developing generic drugs such as biosimilars. Recent developments have focused on analytical methods and statistical approaches to test similarity between mixtures. The question of how much uncertainty on mixture composition is reduced by combining several measurements still remains mostly unexplored. Mathematical frameworks to combine measurements, estimate mixture properties, and quantify remaining uncertainty, i.e. a characterization extent, are introduced here. Constrained optimization and mathematical modeling are applied to a set of twenty-three experimental measurements on heparan sulfate, a mixture of linear chains of disaccharides having different levels of sulfation. While this mixture has potentially over two million molecular species, mathematical modeling and the small set of measurements establish the existence of nonhomogeneity of sulfate level along chains and the presence of abundant sulfate repeats. Constrained optimization yields not only estimations of sulfate repeats and sulfate level at each position in the chains but also bounds on these levels, thereby estimating the extent of characterization of the sulfation pattern which is achieved by the set of measurements.
Momenta Pharmaceuticals Inc., Research Department, Cambridge, MA 02142, USA.
Joël R
JR
Pradines
Momenta Pharmaceuticals Inc., Research Department, Cambridge, MA 02142, USA.
Daniela
D
Beccati
Momenta Pharmaceuticals Inc., Research Department, Cambridge, MA 02142, USA.
Miroslaw
M
Lech
Momenta Pharmaceuticals Inc., Research Department, Cambridge, MA 02142, USA.
Jennifer
J
Ozug
Momenta Pharmaceuticals Inc., Research Department, Cambridge, MA 02142, USA.
Victor
V
Farutin
Momenta Pharmaceuticals Inc., Research Department, Cambridge, MA 02142, USA.
Yongqing
Y
Huang
Momenta Pharmaceuticals Inc., Research Department, Cambridge, MA 02142, USA.
Nur Sibel
NS
Gunay
Momenta Pharmaceuticals Inc., Research Department, Cambridge, MA 02142, USA.
Ishan
I
Capila
D016568:Drugs, Generic; D019763:Heparin Lyase / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry* / Q000378:metabolism; D008962:Models, Theoretical; D013431:Sulfates / Q000032:analysis
D016568:Drugs, Generic; D019763:Heparin Lyase; D006497:Heparan Sulfate; D013431:Sulfates