title: Structure based descriptors for the estimation of colloidal interactions and protein aggregation propensities.
abstract: The control of protein aggregation is an important requirement in the development of bio-pharmaceutical formulations. Here a simple protein model is proposed that was used in molecular dynamics simulations to obtain a quantitative assessment of the relative contributions of proteins' net-charges, dipole-moments, and the size of hydrophobic or charged surface patches to their colloidal interactions. The results demonstrate that the strength of these interactions correlate with net-charge and dipole moment. Variation of both these descriptors within ranges typical for globular proteins have a comparable effect. By comparison no clear trends can be observed upon varying the size of hydrophobic or charged patches while keeping the other parameters constant. The results are discussed in the context of experimental literature data on protein aggregation. They provide a clear guide line for the development of improved algorithms for the prediction of aggregation propensities.
authors.affiliation: Research Center Pharmaceutical Engineering, Graz, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Brunsteiner
authors.forename: Michaela
authors.initials: M
authors.lastname: Flock
authors.forename: Bernd
authors.initials: B
authors.lastname: Nidetzky
mesh_terms: D000465:Algorithms; D003102:Colloids; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D011506:Proteins / Q000737:chemistry*; D012995:Solubility; D055672:Static Electricity
chemical_list: D003102:Colloids; D011506:Proteins
references.citation: Biopolymers. 1993 Jan;33(1):59-68
references.pmid: 8427939
references.citation: J Pharm Sci. 2010 Feb;99(2):645-62
references.pmid: 19653264
references.citation: J Mol Biol. 2012 Aug 10;421(2-3):237-41
references.pmid: 22172487
references.citation: J Pharm Sci. 2010 Dec;99(12):4830-48
references.pmid: 20821389
references.citation: Phys Rev A Gen Phys. 1985 Mar;31(3):1695-1697
references.pmid: 9895674
references.citation: Curr Opin Struct Biol. 2006 Feb;16(1):118-26
references.pmid: 16434184
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13296-300
references.pmid: 19666545
references.citation: Biophys J. 2003 Aug;85(2):686-94
references.pmid: 12885620
references.citation: J Phys Chem B. 2010 Jan 21;114(2):993-1003
references.pmid: 20039620
references.citation: J Chem Phys. 2012 Feb 21;136(7):074507
references.pmid: 22360248
references.citation: Microb Inform Exp. 2011 Jun 27;1(1):6
references.pmid: 22587847
references.citation: J Chem Theory Comput. 2011 Jul 12;7(7):2284-95
references.pmid: 26606496
references.citation: Protein Sci. 2003 May;12(5):903-13
references.pmid: 12717013
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4201-6
references.pmid: 19251648
references.citation: J Mol Biol. 2008 Jul 4;380(2):425-36
references.pmid: 18514226
references.citation: J Chem Theory Comput. 2008 Mar;4(3):435-47
references.pmid: 26620784
references.citation: J Pharm Sci. 2012 Jan;101(1):102-15
references.pmid: 21935950
references.citation: J Pharm Sci. 2012 Aug;101(8):2720-32
references.pmid: 22648863
references.citation: Biophys J. 1995 Oct;69(4):1344-54
references.pmid: 8534804
references.citation: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W522-5
references.pmid: 17488841
references.citation: J Comput Aided Mol Des. 2010 Nov;24(11):907-16
references.pmid: 20842408
references.citation: Protein Sci. 2004 Jul;13(7):1939-41
references.pmid: 15169952
references.citation: Mol Pharm. 2012 Apr 2;9(4):696-707
references.pmid: 22263524
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11937-42
references.pmid: 19571001
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references.pmid: 10592235
references.citation: J Mol Biol. 2008 Feb 1;375(5):1416-33
references.pmid: 18083189
references.citation: Nat Rev Immunol. 2010 May;10(5):345-52
references.pmid: 20414207
references.citation: Pharm Res. 2011 Aug;28(8):1973-83
references.pmid: 21491149
references.citation: Methods Enzymol. 2003;374:461-91
references.pmid: 14696385
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D71-5
references.pmid: 22102590
references.citation: Hum Mutat. 2009 May;30(5):703-14
references.pmid: 19267389
references.citation: Pharm Res. 2009 Dec;26(12):2607-18
references.pmid: 19795191
references.citation: Biophys J. 2003 Nov;85(5):2940-7
references.pmid: 14581196
references.citation: Mol Pharm. 2012 Apr 2;9(4):791-802
references.pmid: 22352470
references.citation: Biophys Chem. 2012 Jul;168-169:19-27
references.pmid: 22750560
references.citation: J Mol Biol. 1977 May 25;112(3):535-42
references.pmid: 875032
references.citation: Protein Eng Des Sel. 2007 Oct;20(10):521-3
references.pmid: 17720750
references.citation: Anal Biochem. 2004 Feb 1;325(1):1-20
references.pmid: 14715279
references.citation: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W512-21
references.pmid: 17526523
references.citation: Biophys J. 2001 Feb;80(2):613-25
references.pmid: 11159430
references.citation: J Pharm Sci. 2012 Mar;101(3):998-1011
references.pmid: 22113861
references.citation: Nat Biotechnol. 2010 Sep;28(9):917-24
references.pmid: 20829826
references.citation: Biophys J. 2012 Jul 3;103(1):69-78
references.pmid: 22828333
references.citation: J Comput Chem. 2002 Apr 30;23(6):600-9
references.pmid: 11939594
references.citation: J Pharm Sci. 2012 Apr;101(4):1400-9
references.pmid: 22234888
references.citation: J Mol Biol. 2007 Feb 16;366(2):449-60
references.pmid: 17174328
references.citation: Nat Biotechnol. 2004 Oct;22(10):1302-6
references.pmid: 15361882
references.citation: J Chem Theory Comput. 2011 Feb 8;7(2):525-37
references.pmid: 26596171
references.citation: J Pharm Sci. 2011 Jul;100(7):2551-62
references.pmid: 21294130
references.citation: Nature. 2003 Aug 14;424(6950):805-8
references.pmid: 12917692
references.citation: Phys Chem Chem Phys. 2009 Oct 21;11(39):8879-85
references.pmid: 20449034
references.citation: Int J Pharm. 2011 Dec 12;421(1):82-93
references.pmid: 21959107
references.citation: Mol Pharm. 2012 Mar 5;9(3):622-8
references.pmid: 22304418