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 ,

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

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

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

5. Top Lattice Structures

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

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

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

11. Energy gap vs. Ns

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

13. Design Protocol