title: Trastuzumab-Peptide interactions: mechanism and application in structure-based ligand design.
abstract: Understanding of protein-ligand interactions and its influences on protein stability is necessary in the research on all biological processes and correlative applications, for instance, the appropriate affinity ligand design for the purification of bio-drugs. In this study, computational methods were applied to identify binding site interaction details between trastuzumab and its natural receptor. Trastuzumab is an approved antibody used in the treatment of human breast cancer for patients whose tumors overexpress the HER2 (human epidermal growth factor receptor 2) protein. However, rational design of affinity ligands to keep the stability of protein during the binding process is still a challenge. Herein, molecular simulations and quantum mechanics were used on protein-ligand interaction analysis and protein ligand design. We analyzed the structure of the HER2-trastuzumab complex by molecular dynamics (MD) simulations. The interaction energies of the mutated peptides indicate that trastuzumab binds to ligand through electrostatic and hydrophobic interactions. Quantitative investigation of interactions shows that electrostatic interactions play the most important role in the binding of the peptide ligand. Prime/MM-GBSA calculations were carried out to predict the binding affinity of the designed peptide ligands. A high binding affinity and specificity peptide ligand is designed rationally with equivalent interaction energy to the wild-type octadecapeptide. The results offer new insights into affinity ligand design.
authors: Soft Matter Research Center, Department of Chemistry, Zhejiang University, Hangzhou 310027, China. suntyy@gmail.com
authors: Tian-Yang
authors: TY
authors: Sun
authors: Qi
authors: Q
authors: Wang
authors: Jin
authors: J
authors: Zhang
authors: Tao
authors: T
authors: Wu
authors: Fan
authors: F
authors: Zhang
mesh_terms: D000595:Amino Acid Sequence; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism*; D001665:Binding Sites; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D055672:Static Electricity; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007140:Immunoglobulin Fab Fragments; D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
references: Proteins. 2010 May 15;78(7):1705-23
references: 20186976
references: Cancer Biother Radiopharm. 1999 Feb;14(1):5-10
references: 10850281
references: Nature. 2003 Feb 13;421(6924):756-60
references: 12610629
references: Biomaterials. 2008 May;29(15):2423-32
references: 18299149
references: J Mol Biol. 2005 Feb 4;345(5):1281-94
references: 15644221
references: J Phys Chem B. 2011 Oct 20;115(41):11902-10
references: 21899337
references: J Chromatogr A. 2012 Feb 17;1225:158-67
references: 22251884
references: Cancer Res. 1998 Jul 1;58(13):2825-31
references: 9661897
references: Proteins. 2007 Sep 1;68(4):803-12
references: 17546660
references: Science. 1990 Jul 27;249(4967):386-90
references: 1696028
references: J Biol Chem. 2010 Aug 6;285(32):24729-39
references: 20516066
references: Proc Natl Acad Sci U S A. 1990 Aug;87(16):6378-82
references: 2201029
references: Biomaterials. 2008 Feb;29(5):513-32
references: 17988731
references: Biosens Bioelectron. 2007 Apr 15;22(9-10):1939-47
references: 16996258
references: Nature. 2000 Feb 10;403(6770):623-7
references: 10688190
references: J Comput Chem. 2005 Dec;26(16):1781-802
references: 16222654
references: J Proteome Res. 2011 Nov 4;10(11):4948-58
references: 21905665
references: J Phys Chem B. 1998 Apr 30;102(18):3586-616
references: 24889800
references: J Mol Biol. 2004 Feb 27;336(4):943-55
references: 15095871
references: Nature. 1991 Nov 7;354(6348):82-4
references: 1944576
references: Science. 1990 Jul 27;249(4967):404-6
references: 2143033
references: J Med Chem. 2006 Aug 10;49(16):4805-8
references: 16884290
references: J Chromatogr A. 2007 Aug 10;1160(1-2):44-55
references: 17618635
references: Nature. 1989 Jul 20;340(6230):245-6
references: 2547163
references: Chem Rev. 1997 Apr 1;97(2):411-448
references: 11848877
references: Protein Sci. 2003 Jul;12(7):1496-506
references: 12824495
references: J Phys Chem B. 2011 Nov 17;115(45):13320-7
references: 21942536
references: Biomaterials. 2009 May;30(14):2807-15
references: 19200595
references: Protein Sci. 2008 Apr;17(4):652-63
references: 18305195
references: J Chromatogr A. 2009 Feb 6;1216(6):910-8
references: 19117576
references: J Recept Signal Transduct Res. 2003;23(4):307-49
references: 14753295
references: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18491-6
references: 19833875
references: Protein Sci. 2007 Apr;16(4):582-8
references: 17384226
references: Chem Biol Drug Des. 2009 Sep;74(3):246-57
references: 19703026