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Protein Design Based on the Designability of Protein Structures

Protein Design Based on the Designability of Protein Structures. Chen Zeng, PI (GWU) Chao Tang, Co-PI (NEC) Ned Wingreen (Princeton) Naigong Zhang (GWU) Luhua Lai (PKU) NSF Support: DMR-0094176, 0313129. Protein Folds (~1000! Why so small?). Acylphosphatase. Ribosomal protein S6.

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Protein Design Based on the Designability of Protein Structures

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  1. Protein Design Based on the Designability of Protein Structures Chen Zeng, PI (GWU) Chao Tang, Co-PI (NEC) Ned Wingreen (Princeton) Naigong Zhang (GWU) Luhua Lai (PKU) NSF Support: DMR-0094176, 0313129

  2. Protein Folds (~1000! Why so small?) Acylphosphatase Ribosomal protein S6 Ferredoxin Viral DNA-binding domain

  3. H--Hydrophobic (Dill) P--Polar EHH EPP EHP Hydrophobicity Segregation HP Lattice Model

  4. Sequences (108) Structures (105) Designability NS=1 NS=5 NS=0 NS=2 NS=1 Enumeration (HP Lattice Model)H. Li, C. Tang, N. Wingreen (NEC) 95% sequences have degenerate G-states

  5. Top Lattice Structures

  6. y f Off-Lattice m-State Model Park & Levitt (1995) (f,y) = (f1,y1), (f2,y2), …, (fm,ym)

  7. 1PSV o crms ~ 0.8 A Fit to 1PSV By 3-State Model

  8. Enumeration of Configurations (off-lattice HP model) ai – accessible surface area of residue i A=S ai < Ac H = S hi a’i (a’i=ai/A)

  9. Searching for New Folds MAQTDVILCPDTHQKAVCLEKIR EYFDCGLPSAQWCVIKNALLTFR PNMDKILYVVACQGGARASLTLR GAWETRKLHCMQPIVYTTLNGLT MNSAKPLVVTIYSQYNVHLRFDD GFDSKLACVNPMRTYEIWLETFR MLKSPQCNYIAVRIHGRYLDFGS CVNKMYHGFDAALLTRQVLPSLT QIVLTAGNYIGRGPNIPCLDIGS EFIINCAQLVRENHWGVSGLRAN LAGTRVNIMPCDEWSILSLMKIH FHDISAQVYTERPQMVKRLAFRA TCNMRWDPSIVYTWQFGHLCVHE WMTVINEDSAPILCWHGGLMFGN VVEERPAADIMNWGLRCSLKELT ILKNETVGGAPQWYIVHNQFNAK NQKDIETRYPMKSLVSCILHIKM LMKIHYDTFREWQVNSCKLDDVS MSKALLVPQWIVRCSYTPLKWPS TCNMRWDPSIVYTWQFGHLSLVT CAKVINEDSAPILCTRSGLRLTD VNYIPPAADIAQREMRCSLTNQL VDGHETVGGAPQWYFAKRLCRGA DEYLIETRYPMKSLILSTAEEKL ATDIHYDAGREWQVNSFELITSV ETLDLLVPQWIVRCSHTFDIPQS

  10. o o N=23, rb=1.9 A, l=0.4 A, 10,000 configurations, 4688 clusters Histogram of Ns

  11. Energy gap vs. Ns

  12. II. Pick Top Folds Design Procedure I. Model Computation III. Sequence Design and Verification bab motif 2bnh 2nac

  13. Design Protocol

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