Bi1_2009_Lecture23_full

Combinatorial optimization algorithms negative design

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Unformatted text preview: Libraries Protein Backbones Combinatorial Optimization Algorithms Negative Design Computational Protein Design Optimization of Rotamers by Iterative Techniques (ORBIT) Apply to protein fold stabilization, enzyme design Applications Mayo lab, Caltech De Novo Protein Design: Fully automated sequence selection Dahiyat & Mayo, 1997, Science 278: 82-87 Designed protein Zif268 Zn finger Target fold: Zif268 (a zinc finger) Comparison of original and designed protein structures Stability Based Design: Protein G • Bacterial protein involved in host immune system evasion 56 amino acid domain Objective was to stabilize protein while preserving structure and function Design focused on 26 core and boundary positions Combinatorial complexity, 106 amino acid sequences Mayo lab, Caltech • • • • Kemp Elimination: a model system for enzyme design O O O H O HO N O H O2N N O O2N N O C O2N O- 5-nitrobenzsoxazole catalytic antibody: kcat/kuncat = 106 ab initio t.s. model active site template General Base Asp/Glu O H O O N * * Phe/Trp N O O H-bond donor Hie/Hid/Gln/Asn HN N H O H-bond donor Ser/Thr/Tyr Thorn et al., Nature 1995 Debler et al., PNAS 2005 Hu et al., JACS 2004 Mayo lab, Caltech...
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